- Email: [email protected]
In a Class of Its Own: A New Family of Deubiquitinases Promotes Genome Stability
Molecular Cell
Previews In a Class of Its Own: A New Family of Deubiquitinases Promotes Genome Stability Kate E. Coleman1 and Tony T. Huang1,* 1Department of Biochemistry & Molecular Pharmacology, New York University School of Medicine, New York, NY 10016, USA *Correspondence: [email protected] https://doi.org/10.1016/j.molcel.2018.03.022
Several proteins are ubiquitylated in response to genotoxic stress; however, the roles of deubiquitinases (DUBs) in reversing these modifications are less well characterized. Two independent studies by Kwasna et al. (2018) and Haahr et al. (2018) identify a new type of cysteine protease DUB called ZUFSP, which cleaves K63-linked polyubiquitin chains at DNA damage sites to promote genome stability. In response to various genotoxic agents, cells evoke an elaborate signaling network called the DNA damage response (DDR) to sense and direct downstream cellular responses to DNA damage (Ciccia and Elledge, 2010). Large-scale proteomic screens have revealed that dynamic changes in protein post-translational modifications (PTMs)— such as phosphorylation, acetylation, and ubiquitylation—are critical to efficient DDR signaling (Elia et al., 2015). In particular, the addition of ubiquitin (Ub) modifications to acceptor lysine residues in target proteins can play several functional roles during the DDR, including recruitment of interacting protein partners, changing protein activity, and targeting proteins for degradation by the 26S proteasome (Huang and D’Andrea, 2006). These activities are often directed by either monoubiquitylation or polyubiquitin (polyUb) chains of different linkages. For example, K11- and K48-linked chains most often signal for proteasomal degradation, whereas K63-linked ubiquitylation is commonly a non-proteolytic modification (Komander and Rape, 2012). While numerous ubiquitin modifications of different linkages have been identified in response to DNA damage, their individual functional roles are only beginning to be discovered. Another important aspect is that these ubiquitin modifications must be reversed in a timely manner to mediate recovery from DNA damage through the action of deubiquitylating enzymes (DUBs), about 100 of which are encoded by the human genome. Several DUBs have already been shown to regulate DNA repair and DNA damage responses in human cells (Kee and Huang, 2015).
Nevertheless, our understanding of the complete repertoire of DUBs and relevant ubiquitylated substrates involved in this context, as well as the mechanisms for DUB specificity during the DDR, is currently limited. In an effort to discover new DUBs with potential roles in the DDR, two papers in this issue by Haahr et al. (2018) and Kwasna et al., (2018) uncovered a new class of cysteine protease DUB called ZUFSP (zinc finger with UFM1-specific peptidase domain protein), which has no homology to any other known DUBs. Originally, ZUFSP was annotated as a potentially inactive protease for the ubiquitin-like modifier UFM1. However, while its peptidase domain shows homology to known UFM1 proteases, it conspicuously lacks a key catalytic histidine residue needed for UFM1 cleavage. ZUFSP also contains a ubiquitin-binding domain (UBD) called a motif interacting with ubiquitin (MIU) that is found in several proteins with important roles in ubiquitin-mediated signaling (Husnjak and Dikic, 2012), further indicating that ZUFSP could be reactive toward ubiquitin rather than UFM1. To support the fact that ZUFSP has intrinsic DUB activity, both the Mailand and Kulathu groups showed that ZUFSP is readily modified by a ubiquitin-specific activity-based probe (Ub-Prg or Ub-VS), which irreversibly reacts with active site cysteine residues in DUBs (Ekkebus et al., 2014). By contrast, ZUFSP could not be covalently trapped by either SUMO1-VS or UFM1-Prg, suggesting that ZUFSP is specific to ubiquitin chains (Haahr et al., 2018; Kwasna et al., 2018). In light of these
and other findings, the name ZUFSP is actually a misnomer, and the renaming of this protein to ZUP (zinc finger containing ubiquitin peptidase) has been proposed. One of the unique characteristics of ZUFSP that both the Mailand and Kulathu labs uncovered is that it is highly selective toward K63-linked polyubiquitin chains. In particular, ZUFSP has a strong preference for long K63-linked chains (> tetra Ub) and shows minimal activity toward mono- or di-Ub substrates (Haahr et al., 2018; Kwasna et al., 2018). This is a novel feature, as the vast majority of DUBs are non-selective and will cleave most types of polyUb linkages (Faesen et al., 2011). The Mailand and Kulathu labs offer different molecular requirements for Ub recognition and catalysis of K63-linked chains by ZUFSP, which are summarized in Figure 1. For example, the Haahr et al. (2018) paper attributes the specific Ub-binding activity of this DUB to tandem UBDs (including a MIU and an immediately proximal UBZ domain) that cooperatively confer high affinity binding to polyUb chains. Point mutations in either the MIU or UBZ domains severely compromised the binding of ZUFSP to K63-linked polyUb chains, indicating the importance of both of these motifs to Ub recognition by ZUFSP (Haahr et al., 2018). In a different approach, the Kulathu lab solved the crystal structure of the ZUFSP minimal catalytic domain plus its MIU in complex with the Ub-Prg probe. Based on this structure and additional polyUb binding and cleavage assays, the authors identified two motifs in ZUFSP that could be used to recognize the distal Ub (S1) and
Molecular Cell 70, April 5, 2018 ª 2018 Elsevier Inc. 1
Molecular Cell
Previews proximal Ub (S10 ) of K63linked polyUb chains positioned across the DUB active site: a ZUFSP helical arm (ZHA) for S1 binding site and an atypical UBZ domain for S10 binding site that aligns K63-linked polyUb for cleavage. No extensive contacts between the MIU of ZUFSP and Ub were observed in the crystal structure, although the MIU was determined to be required for optimal polyUb chain cleavage (Kwasna et al., 2018). They speculate that the MIU may contribute to the S2 binding site for K63-linked polyUb binding. Interestingly, the authors further showed that, when UFM1 is superimposed onto Ub in this structure, equivalent residues at the C terminus of UFM1 sterically clash with the ZHA such that they cannot be accommodated within the narrow catalytic groove of ZUFSP (Kwasna et al., 2018). These observations partially explain why ZUFSP is inactive as a UFM1 protease and instead has DUB activity. As it was previously shown that ZUFSP co-purifies with et al., RPA subunits (Tka´c 2016), both the Mailand and Kulathu groups speculated that ZUFSP may function in genome maintenance pathways. Accordingly, both groups showed that ZUFSP localizes to sites of DNA damage and that maximal accumulation of ZUFSP at genotoxic stress sites is dependent on Ubc13, the major E2-Ub-conjugating enzyme responsible for K63 chain formation (Hofmann and Pickart, 1999). A variety of defects were observed in ZUFSP-deficient cells, including increased sensitivity to DNA damaging agents and other markers for genome instability such as elevated
2 Molecular Cell 70, April 5, 2018
A
B
micronuclei formation and S-phase-associated DNA damage (Haahr et al., 2018; Kwasna et al., 2018). Taken together, these results suggest that ZUFSP plays an important role in modulating genome maintenance pathways through limiting K63linked polyUb chain formation at sites of DNA damage. Following the discovery and characterization of ZUFSP, several open questions remain: For example, what are the substrates of ZUFSP, and what are their respective roles in the DDR? How does the deubiquitylation of these proteins allow for efficient recovery from genotoxic stress? Why does ZUFSP prefer long K63-linked Ub chains? Does ZUFSP loss synergize with defects in specific DDR pathways? More work will be required to address these and other outstanding questions regarding the physiological role and biochemical activity of ZUFSP. Nevertheless, the work from Haahr et al. (2018) and Kwasna et al. (2018) provides another example of the importance of DUBs in DNA replication and repair processes. As DUBs are commonly dysregulated in a wide range of human cancers, there has been growing interest in exploring DUBs as druggable targets. Thus, increased understanding of the specific roles of individual DUBs such as ZUFSP in cell signaling pathways, as well as the functional redundancies between DUBs, is critical for the potential usage of DUB inhibitors for cancer treatment.
Figure 1. ZUFSP Promotes Genome Stability by Selectively Cleaving K63-Linked PolyUb Chains at DNA Damage Sites (A) Evidence from both the Mailand and Kulathu labs show that ZUFSP deubiquitylates substrates bearing K63-linked polyUb chains to maintain chromosome stability. (B) Models for Ub recognition by ZUFSP. The Mailand lab demonstrates that tandem MIU and UBZ motifs within ZUFSP are necessary for K63-linked polyUb chain recognition and cleavage. The Kulathu lab proposes a model
for substrate binding and catalysis by ZUFSP whereby a helical arm called a ZHA domain forms the S1 site for distal Ub recognition, whereas a UBZ domain (ZnF4) provides the S10 site for proximal Ub.
Molecular Cell
Previews REFERENCES Ciccia, A., and Elledge, S.J. (2010). The DNA damage response: making it safe to play with knives. Mol. Cell 40, 179–204. Ekkebus, R., Flierman, D., Geurink, P.P., and Ovaa, H. (2014). Catching a DUB in the act: novel ubiquitin-based active site directed probes. Curr. Opin. Chem. Biol. 23, 63–70. Elia, A.E.H., Boardman, A.P., Wang, D.C., Huttlin, E.L., Everley, R.A., Dephoure, N., Zhou, C., Koren, I., Gygi, S.P., and Elledge, S.J. (2015). Quantitative Proteomic Atlas of Ubiquitination and Acetylation in the DNA Damage Response. Mol. Cell 59, 867–881. Faesen, A.C., Luna-Vargas, M.P.A., Geurink, P.P., Clerici, M., Merkx, R., van Dijk, W.J., Hameed, D.S., El Oualid, F., Ovaa, H., and Sixma, T.K. (2011). The differential modulation of USP activity by internal regulatory domains, interactors and eight ubiquitin chain types. Chem. Biol. 18, 1550–1561. Haahr, P., Borgermann, N., Guo, X., Typas, D., Achuthankutty, D., Hoffman, S., Shearer, R., Sixma, T., and Mailand, N. (2018). ZUFSP deubiquitylates
K63-linked polyubiquitin chains to promote genome stability. Mol. Cell 70, this issue, 165–174. Hofmann, R.M., and Pickart, C.M. (1999). Noncanonical MMS2-encoded ubiquitin-conjugating enzyme functions in assembly of novel polyubiquitin chains for DNA repair. Cell 96, 645–653. Huang, T.T., and D’Andrea, A.D. (2006). Regulation of DNA repair by ubiquitylation. Nat. Rev. Mol. Cell Biol. 7, 323–334. Husnjak, K., and Dikic, I. (2012). Ubiquitin-binding proteins: decoders of ubiquitin-mediated cellular functions. Annu. Rev. Biochem. 81, 291–322. Kee, Y., and Huang, T.T. (2015). The role of deubiquitinating enzymes in DNA repair. Mol. Cell. Biol., 00847-15. Komander, D., and Rape, M. (2012). The ubiquitin code. Annu. Rev. Biochem. 81, 203–229. Kwasna, D., Rehman, S.A.A., Natarajan, J., Matthews, S., Madden, R., De Cesare, V., Weidlich, S., Virdee, S., Ahel, I., Gibbs Seymour, I., et al. (2018). Discovery and characterization of
ZUFSP, a novel DUB class important for genome stability. Mol. Cell 70, this issue, 150–164. , J., Xu, G., Adhikary, H., Young, J.T.F., Gallo, Tka´c D., Escribano-Dı´az, C., Krietsch, J., Orthwein, A., Munro, M., Sol, W., et al. (2016). HELB is a feedback inhibitor of DNA end resection. Mol. Cell 61, 405–418.
Note Added in Proof Since the submission of this manuscript, two additional papers featuring similar observations have been published. They are as follows: Hermanns, T., Pichlo, C., Woiwode, I., Klopffleisch, K., Witting, K.F., Ovaa, H., Baumann, U., and Hofmann, K. A family of unconventional deubiquitinases with modular chain specificity determinants. Nat. Commun. 9, 799. Hewings, D.S., Heideker, J., Ma, T.P., AhYoung, A.P., El Oualid, F., Amore, A., Costakes, G.T., Kirchhofer, D., Brasher, B., Pillow, T., et al. (2018). Reactive-site-centric chemoproteomics identifies a distinct class of deubiquitinase enzymes. Nat. Commun. 9, 1162.
A Much-Needed Boost for the Dwindling Antibiotic Pipeline Scott C. Blanchard1,* 1Department of Physiology and Biophysics, Weill Cornell Medicine, Belfer Research Building, 413 East 69th Street, New York, NY 10065, USA *Correspondence: [email protected] https://doi.org/10.1016/j.molcel.2018.03.023
In this issue of Molecular Cell, Pantel et al. (2018) identify and synthetically optimize a novel ribosometargeting antimicrobial from a potentially rich new source of bioactive natural products. Since the discovery and clinical implementation of penicillin in the late 1920s, antibiotics have grown to become essential to nearly every aspect of modern medicine (Luepke and Mohr, 2017). But, as the World Health Organization’s Global Antimicrobial Surveillance System (GLASS) reports (World Health Organization, 2017), the growing spread of antibioticresistant pathogens now poses serious threats to human health. Bacterial infections killed nearly 17 million people worldwide in 2006 (Martens and Demain, 2017). In 2013, the Centers for Disease Control conservatively estimated approximately 2 million antibiotic-resistancerelated illnesses in the United States alone—approximately 1% of which result
in patient death—at total annual cost of $50–$70 billion USD (Centers for Disease Control, 2013). At that time, CDC director Tom Frieden noted, ‘‘If we don’t act now, our medicine cabinet will be empty and we won’t have the antibiotics we need to save lives.’’ Alarmingly, common and serious pathogens have since been identified in the clinic that exhibit resistance to nearly all currently available antibiotics (World Health Organization, 2017). A 2016 report from the United Kingdom put the global cost of antibiotic-resistant bacterial infections over the next 35 years at nearly 100 trillion USD (O’Neill, 2016). The combination of a dwindling antibiotic pipeline in the face of growing antimicrobial resistance raises
concern that we are on the brink of a post-antibiotic era (Luepke and Mohr, 2017; Martens and Demain, 2017). Fueling a potentially new pipeline for antimicrobial natural product discovery, Pantel et al. (2018) delve into the pool of natural products produced by the Gramnegative Xenorhabdus nematophila, a bacteria symbiotically associated with soil-dwelling nematodes. In so doing, they identify non-ribosomal peptides, referred to as odilorhabdins (ODLs), which exhibit promising broad-spectrum antibacterial activity against a wide range of Gramnegative and Gram-positive bacterial pathogens, including difficult-to-treat drug-resistant strains. The peptidic nature of ODLs enabled synthetic, chemical
Molecular Cell 70, April 5, 2018 ª 2018 Elsevier Inc. 3
Previews In a Class of Its Own: A New Family of Deubiquitinases Promotes Genome Stability Kate E. Coleman1 and Tony T. Huang1,* 1Department of Biochemistry & Molecular Pharmacology, New York University School of Medicine, New York, NY 10016, USA *Correspondence: [email protected] https://doi.org/10.1016/j.molcel.2018.03.022
Several proteins are ubiquitylated in response to genotoxic stress; however, the roles of deubiquitinases (DUBs) in reversing these modifications are less well characterized. Two independent studies by Kwasna et al. (2018) and Haahr et al. (2018) identify a new type of cysteine protease DUB called ZUFSP, which cleaves K63-linked polyubiquitin chains at DNA damage sites to promote genome stability. In response to various genotoxic agents, cells evoke an elaborate signaling network called the DNA damage response (DDR) to sense and direct downstream cellular responses to DNA damage (Ciccia and Elledge, 2010). Large-scale proteomic screens have revealed that dynamic changes in protein post-translational modifications (PTMs)— such as phosphorylation, acetylation, and ubiquitylation—are critical to efficient DDR signaling (Elia et al., 2015). In particular, the addition of ubiquitin (Ub) modifications to acceptor lysine residues in target proteins can play several functional roles during the DDR, including recruitment of interacting protein partners, changing protein activity, and targeting proteins for degradation by the 26S proteasome (Huang and D’Andrea, 2006). These activities are often directed by either monoubiquitylation or polyubiquitin (polyUb) chains of different linkages. For example, K11- and K48-linked chains most often signal for proteasomal degradation, whereas K63-linked ubiquitylation is commonly a non-proteolytic modification (Komander and Rape, 2012). While numerous ubiquitin modifications of different linkages have been identified in response to DNA damage, their individual functional roles are only beginning to be discovered. Another important aspect is that these ubiquitin modifications must be reversed in a timely manner to mediate recovery from DNA damage through the action of deubiquitylating enzymes (DUBs), about 100 of which are encoded by the human genome. Several DUBs have already been shown to regulate DNA repair and DNA damage responses in human cells (Kee and Huang, 2015).
Nevertheless, our understanding of the complete repertoire of DUBs and relevant ubiquitylated substrates involved in this context, as well as the mechanisms for DUB specificity during the DDR, is currently limited. In an effort to discover new DUBs with potential roles in the DDR, two papers in this issue by Haahr et al. (2018) and Kwasna et al., (2018) uncovered a new class of cysteine protease DUB called ZUFSP (zinc finger with UFM1-specific peptidase domain protein), which has no homology to any other known DUBs. Originally, ZUFSP was annotated as a potentially inactive protease for the ubiquitin-like modifier UFM1. However, while its peptidase domain shows homology to known UFM1 proteases, it conspicuously lacks a key catalytic histidine residue needed for UFM1 cleavage. ZUFSP also contains a ubiquitin-binding domain (UBD) called a motif interacting with ubiquitin (MIU) that is found in several proteins with important roles in ubiquitin-mediated signaling (Husnjak and Dikic, 2012), further indicating that ZUFSP could be reactive toward ubiquitin rather than UFM1. To support the fact that ZUFSP has intrinsic DUB activity, both the Mailand and Kulathu groups showed that ZUFSP is readily modified by a ubiquitin-specific activity-based probe (Ub-Prg or Ub-VS), which irreversibly reacts with active site cysteine residues in DUBs (Ekkebus et al., 2014). By contrast, ZUFSP could not be covalently trapped by either SUMO1-VS or UFM1-Prg, suggesting that ZUFSP is specific to ubiquitin chains (Haahr et al., 2018; Kwasna et al., 2018). In light of these
and other findings, the name ZUFSP is actually a misnomer, and the renaming of this protein to ZUP (zinc finger containing ubiquitin peptidase) has been proposed. One of the unique characteristics of ZUFSP that both the Mailand and Kulathu labs uncovered is that it is highly selective toward K63-linked polyubiquitin chains. In particular, ZUFSP has a strong preference for long K63-linked chains (> tetra Ub) and shows minimal activity toward mono- or di-Ub substrates (Haahr et al., 2018; Kwasna et al., 2018). This is a novel feature, as the vast majority of DUBs are non-selective and will cleave most types of polyUb linkages (Faesen et al., 2011). The Mailand and Kulathu labs offer different molecular requirements for Ub recognition and catalysis of K63-linked chains by ZUFSP, which are summarized in Figure 1. For example, the Haahr et al. (2018) paper attributes the specific Ub-binding activity of this DUB to tandem UBDs (including a MIU and an immediately proximal UBZ domain) that cooperatively confer high affinity binding to polyUb chains. Point mutations in either the MIU or UBZ domains severely compromised the binding of ZUFSP to K63-linked polyUb chains, indicating the importance of both of these motifs to Ub recognition by ZUFSP (Haahr et al., 2018). In a different approach, the Kulathu lab solved the crystal structure of the ZUFSP minimal catalytic domain plus its MIU in complex with the Ub-Prg probe. Based on this structure and additional polyUb binding and cleavage assays, the authors identified two motifs in ZUFSP that could be used to recognize the distal Ub (S1) and
Molecular Cell 70, April 5, 2018 ª 2018 Elsevier Inc. 1
Molecular Cell
Previews proximal Ub (S10 ) of K63linked polyUb chains positioned across the DUB active site: a ZUFSP helical arm (ZHA) for S1 binding site and an atypical UBZ domain for S10 binding site that aligns K63-linked polyUb for cleavage. No extensive contacts between the MIU of ZUFSP and Ub were observed in the crystal structure, although the MIU was determined to be required for optimal polyUb chain cleavage (Kwasna et al., 2018). They speculate that the MIU may contribute to the S2 binding site for K63-linked polyUb binding. Interestingly, the authors further showed that, when UFM1 is superimposed onto Ub in this structure, equivalent residues at the C terminus of UFM1 sterically clash with the ZHA such that they cannot be accommodated within the narrow catalytic groove of ZUFSP (Kwasna et al., 2018). These observations partially explain why ZUFSP is inactive as a UFM1 protease and instead has DUB activity. As it was previously shown that ZUFSP co-purifies with et al., RPA subunits (Tka´c 2016), both the Mailand and Kulathu groups speculated that ZUFSP may function in genome maintenance pathways. Accordingly, both groups showed that ZUFSP localizes to sites of DNA damage and that maximal accumulation of ZUFSP at genotoxic stress sites is dependent on Ubc13, the major E2-Ub-conjugating enzyme responsible for K63 chain formation (Hofmann and Pickart, 1999). A variety of defects were observed in ZUFSP-deficient cells, including increased sensitivity to DNA damaging agents and other markers for genome instability such as elevated
2 Molecular Cell 70, April 5, 2018
A
B
micronuclei formation and S-phase-associated DNA damage (Haahr et al., 2018; Kwasna et al., 2018). Taken together, these results suggest that ZUFSP plays an important role in modulating genome maintenance pathways through limiting K63linked polyUb chain formation at sites of DNA damage. Following the discovery and characterization of ZUFSP, several open questions remain: For example, what are the substrates of ZUFSP, and what are their respective roles in the DDR? How does the deubiquitylation of these proteins allow for efficient recovery from genotoxic stress? Why does ZUFSP prefer long K63-linked Ub chains? Does ZUFSP loss synergize with defects in specific DDR pathways? More work will be required to address these and other outstanding questions regarding the physiological role and biochemical activity of ZUFSP. Nevertheless, the work from Haahr et al. (2018) and Kwasna et al. (2018) provides another example of the importance of DUBs in DNA replication and repair processes. As DUBs are commonly dysregulated in a wide range of human cancers, there has been growing interest in exploring DUBs as druggable targets. Thus, increased understanding of the specific roles of individual DUBs such as ZUFSP in cell signaling pathways, as well as the functional redundancies between DUBs, is critical for the potential usage of DUB inhibitors for cancer treatment.
Figure 1. ZUFSP Promotes Genome Stability by Selectively Cleaving K63-Linked PolyUb Chains at DNA Damage Sites (A) Evidence from both the Mailand and Kulathu labs show that ZUFSP deubiquitylates substrates bearing K63-linked polyUb chains to maintain chromosome stability. (B) Models for Ub recognition by ZUFSP. The Mailand lab demonstrates that tandem MIU and UBZ motifs within ZUFSP are necessary for K63-linked polyUb chain recognition and cleavage. The Kulathu lab proposes a model
for substrate binding and catalysis by ZUFSP whereby a helical arm called a ZHA domain forms the S1 site for distal Ub recognition, whereas a UBZ domain (ZnF4) provides the S10 site for proximal Ub.
Molecular Cell
Previews REFERENCES Ciccia, A., and Elledge, S.J. (2010). The DNA damage response: making it safe to play with knives. Mol. Cell 40, 179–204. Ekkebus, R., Flierman, D., Geurink, P.P., and Ovaa, H. (2014). Catching a DUB in the act: novel ubiquitin-based active site directed probes. Curr. Opin. Chem. Biol. 23, 63–70. Elia, A.E.H., Boardman, A.P., Wang, D.C., Huttlin, E.L., Everley, R.A., Dephoure, N., Zhou, C., Koren, I., Gygi, S.P., and Elledge, S.J. (2015). Quantitative Proteomic Atlas of Ubiquitination and Acetylation in the DNA Damage Response. Mol. Cell 59, 867–881. Faesen, A.C., Luna-Vargas, M.P.A., Geurink, P.P., Clerici, M., Merkx, R., van Dijk, W.J., Hameed, D.S., El Oualid, F., Ovaa, H., and Sixma, T.K. (2011). The differential modulation of USP activity by internal regulatory domains, interactors and eight ubiquitin chain types. Chem. Biol. 18, 1550–1561. Haahr, P., Borgermann, N., Guo, X., Typas, D., Achuthankutty, D., Hoffman, S., Shearer, R., Sixma, T., and Mailand, N. (2018). ZUFSP deubiquitylates
K63-linked polyubiquitin chains to promote genome stability. Mol. Cell 70, this issue, 165–174. Hofmann, R.M., and Pickart, C.M. (1999). Noncanonical MMS2-encoded ubiquitin-conjugating enzyme functions in assembly of novel polyubiquitin chains for DNA repair. Cell 96, 645–653. Huang, T.T., and D’Andrea, A.D. (2006). Regulation of DNA repair by ubiquitylation. Nat. Rev. Mol. Cell Biol. 7, 323–334. Husnjak, K., and Dikic, I. (2012). Ubiquitin-binding proteins: decoders of ubiquitin-mediated cellular functions. Annu. Rev. Biochem. 81, 291–322. Kee, Y., and Huang, T.T. (2015). The role of deubiquitinating enzymes in DNA repair. Mol. Cell. Biol., 00847-15. Komander, D., and Rape, M. (2012). The ubiquitin code. Annu. Rev. Biochem. 81, 203–229. Kwasna, D., Rehman, S.A.A., Natarajan, J., Matthews, S., Madden, R., De Cesare, V., Weidlich, S., Virdee, S., Ahel, I., Gibbs Seymour, I., et al. (2018). Discovery and characterization of
ZUFSP, a novel DUB class important for genome stability. Mol. Cell 70, this issue, 150–164. , J., Xu, G., Adhikary, H., Young, J.T.F., Gallo, Tka´c D., Escribano-Dı´az, C., Krietsch, J., Orthwein, A., Munro, M., Sol, W., et al. (2016). HELB is a feedback inhibitor of DNA end resection. Mol. Cell 61, 405–418.
Note Added in Proof Since the submission of this manuscript, two additional papers featuring similar observations have been published. They are as follows: Hermanns, T., Pichlo, C., Woiwode, I., Klopffleisch, K., Witting, K.F., Ovaa, H., Baumann, U., and Hofmann, K. A family of unconventional deubiquitinases with modular chain specificity determinants. Nat. Commun. 9, 799. Hewings, D.S., Heideker, J., Ma, T.P., AhYoung, A.P., El Oualid, F., Amore, A., Costakes, G.T., Kirchhofer, D., Brasher, B., Pillow, T., et al. (2018). Reactive-site-centric chemoproteomics identifies a distinct class of deubiquitinase enzymes. Nat. Commun. 9, 1162.
A Much-Needed Boost for the Dwindling Antibiotic Pipeline Scott C. Blanchard1,* 1Department of Physiology and Biophysics, Weill Cornell Medicine, Belfer Research Building, 413 East 69th Street, New York, NY 10065, USA *Correspondence: [email protected] https://doi.org/10.1016/j.molcel.2018.03.023
In this issue of Molecular Cell, Pantel et al. (2018) identify and synthetically optimize a novel ribosometargeting antimicrobial from a potentially rich new source of bioactive natural products. Since the discovery and clinical implementation of penicillin in the late 1920s, antibiotics have grown to become essential to nearly every aspect of modern medicine (Luepke and Mohr, 2017). But, as the World Health Organization’s Global Antimicrobial Surveillance System (GLASS) reports (World Health Organization, 2017), the growing spread of antibioticresistant pathogens now poses serious threats to human health. Bacterial infections killed nearly 17 million people worldwide in 2006 (Martens and Demain, 2017). In 2013, the Centers for Disease Control conservatively estimated approximately 2 million antibiotic-resistancerelated illnesses in the United States alone—approximately 1% of which result
in patient death—at total annual cost of $50–$70 billion USD (Centers for Disease Control, 2013). At that time, CDC director Tom Frieden noted, ‘‘If we don’t act now, our medicine cabinet will be empty and we won’t have the antibiotics we need to save lives.’’ Alarmingly, common and serious pathogens have since been identified in the clinic that exhibit resistance to nearly all currently available antibiotics (World Health Organization, 2017). A 2016 report from the United Kingdom put the global cost of antibiotic-resistant bacterial infections over the next 35 years at nearly 100 trillion USD (O’Neill, 2016). The combination of a dwindling antibiotic pipeline in the face of growing antimicrobial resistance raises
concern that we are on the brink of a post-antibiotic era (Luepke and Mohr, 2017; Martens and Demain, 2017). Fueling a potentially new pipeline for antimicrobial natural product discovery, Pantel et al. (2018) delve into the pool of natural products produced by the Gramnegative Xenorhabdus nematophila, a bacteria symbiotically associated with soil-dwelling nematodes. In so doing, they identify non-ribosomal peptides, referred to as odilorhabdins (ODLs), which exhibit promising broad-spectrum antibacterial activity against a wide range of Gramnegative and Gram-positive bacterial pathogens, including difficult-to-treat drug-resistant strains. The peptidic nature of ODLs enabled synthetic, chemical
Molecular Cell 70, April 5, 2018 ª 2018 Elsevier Inc. 3