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Convalescence by temporary senescence
HEADLINES
cytosolic tail of CD1 b was responsible for this higher rate of endocytosis as it contained a YXXZ (Z is any hydrophobic residue) motif. A truncation mutant of CD1 b in which the YXXZ motif was deleted was assayed for its ability to be endocytosed and was found to be endocytosed only poorly compared with wild-type CD1 b. Furthermore, although there was a detectable intracellular pool of the truncated CD1 b, it no longer significantly colocalized with HLA-DM. Thus Sugita and colleagues claim that the YXXZ motif in CD1 b directs its endocytosis and subsequent delivery to the MIIC. In many ways, however, this study raises more questions than it answers. For instance, is the cytosolic tail of CD1 b sufficient to direct a reporter molecule to the MIIC? And how does the cellular machinery differentiate between CD1 b that is destined for the MliC and, say, TGN38 that is delivered to the tram Colgi network (TCN) with the aid of a YQRL motif in its cytosolic tail, and what is the role for the spacing of the YXXZ motif from the transmembrane domain? No doubt, future studies will resolve these issues then we will know ‘the how and the Y’ of endocytosis.
export, defining the consensus sequence as Leu-X,,-Phe/ Ile/Leu/Val/Met-X,_,-Leu-X-lle/Val. Similar NES domains are also being sought in related retroviruses. The paper from Meyer and colleagues defines the NES found in the Rev-like proteins of visna virus, a retrovirus of sheep, and equine infectious anaemia virus. While showing a requirement for leucine/isoleucine residues, neither of these two Rev-like molecules fits the precise consensus defined by Bogerd et al., although the NES of visna virus Rev is exquisitely close, with only a conservative change in the first amino acid (Met instead of Leu). The identification of NES domains is another example of using comparative virology to shed light on fundamental cellular activities.
r
Convalescence by temporary senescence fr
Homing
in on nuclear
export
BOGERD,
H. P., FRIDELL, R. A., BENSON, R. E. and CULLEN, B. R. (1996) Protein sequence requirements for function of the human T-cell leukemia virus type 1 Rex nuclear export signal delineated by a novel in viva randomization selection assay Mol. Cell. Biol. 16, 4207-4214 MEYER, 6. E., MEINKOTH, j. L. and MALIM, M. E. (1996) Nuclear transport of human immunodeficiency virus type 1, visna virus, and equine infectious anemia virus Rev proteins: identification of a family of transferable nuclear export signals
1. Virol. 70, 2350-2359 The identification of consensus sequences for nuclear import has played a major contribution in our understanding of nuclear transport. More recently, studies have focused on the identification of complimentary sequences for nuclear export, and two major types of nuclear-export signal (NES) have been found. The first is the M9 domain of the hnRNP Al protein, a relatively long (40 residue), glycinerich sequence. The second was identified in the Rev/Rex family proteins, which mediate nuclear export of retrovirus genomes, and in protein kinase inhibitor (PKI) a. In these NESS leucine and isoleucine residues are critical for function, but precise consensus sequences have not yet been delineated. Bogerd et al. define the amino acid requirements of the NES of the Rex protein from the pathogenic retrovirus human T-cell leukaemia virus type 1 (HTLV-1). Human immunodeficiency virus 1 (HIV-l) Rev and HTLV-1 Rex are closely related and bind to a nuclear receptor molecule (the Rev/Rex activation domain-binding protein, or Rab - not to be confused with the Rab family of small GTPases). The authors screened an array of different mutants of the Rex NES and monitored both interaction with Rab and nuclear trends
in CELL BIOLOGY
(Vol.
6) October
1996
WANG, X-Z. er al. (1996) Signals from the stressed endoplasmic reticulum C/EBP homologous protein (CHOP/GADD153)
induce
Mol. Cell. Biol. 16, 4273-4280 The transcriptional regulator GADDl53/CHOP had been isolated in two independent ways: as one of a subset of proteins induced by DNA damage whose expression also correlated with starvation-induced growth arrest, and as a dominant-negative inhibitor of the differentiationassociated family of transcription factors C/EBP. Unlike other growth regulators, CHOP appeared to inhibit proliferation, but without promoting differentiation. This apparent paradox may now be solved: the data of Wang and colleagues show that the apparent induction of CHOP expression in response to starvation or DNA damage is in fact due to a response to a different type of cellular stress: the presence of improperly folded proteins in the endoplasmic reticulum (ER). This pathway, called the unfolded-protein response (UPR), involves the transcriptional upregulation of chaperones such as BiP. In vivo, the UPR can be induced by various means, such as glucose starvation or treatment of cells with tunicamycin, both of which inhibit protein glycosylation. Wang et al. show clearly that CHOP is also induced by these treatments and, conversely, that those treatments that had been shown previously to induce CHOP (namely DNA damage and glucose starvation) also induce the UPR. Furthermore, in cells overexpressing BiP, the induction of the UPR by tunicamycin and by DNA damage is attenuated, as is the induction of CHOP, suggesting that the induction of CHOP is indeed correlated with activation of the UPR. Finally, even under conditions of DNA damage that lead to the activation of the tumour-suppressor protein ~53 or stress-activated protein kinases, CHOP is not consistently induced, showing that the DNA-damage response and the UPR are independent. Stress often has unexpected effects, and, while these data remove CHOP from one pathway, this protein may still be at the centre of a response serving to prevent sick cells from embarking on challenging paths, such as growth or differentiation, until health returns.
379
cytosolic tail of CD1 b was responsible for this higher rate of endocytosis as it contained a YXXZ (Z is any hydrophobic residue) motif. A truncation mutant of CD1 b in which the YXXZ motif was deleted was assayed for its ability to be endocytosed and was found to be endocytosed only poorly compared with wild-type CD1 b. Furthermore, although there was a detectable intracellular pool of the truncated CD1 b, it no longer significantly colocalized with HLA-DM. Thus Sugita and colleagues claim that the YXXZ motif in CD1 b directs its endocytosis and subsequent delivery to the MIIC. In many ways, however, this study raises more questions than it answers. For instance, is the cytosolic tail of CD1 b sufficient to direct a reporter molecule to the MIIC? And how does the cellular machinery differentiate between CD1 b that is destined for the MliC and, say, TGN38 that is delivered to the tram Colgi network (TCN) with the aid of a YQRL motif in its cytosolic tail, and what is the role for the spacing of the YXXZ motif from the transmembrane domain? No doubt, future studies will resolve these issues then we will know ‘the how and the Y’ of endocytosis.
export, defining the consensus sequence as Leu-X,,-Phe/ Ile/Leu/Val/Met-X,_,-Leu-X-lle/Val. Similar NES domains are also being sought in related retroviruses. The paper from Meyer and colleagues defines the NES found in the Rev-like proteins of visna virus, a retrovirus of sheep, and equine infectious anaemia virus. While showing a requirement for leucine/isoleucine residues, neither of these two Rev-like molecules fits the precise consensus defined by Bogerd et al., although the NES of visna virus Rev is exquisitely close, with only a conservative change in the first amino acid (Met instead of Leu). The identification of NES domains is another example of using comparative virology to shed light on fundamental cellular activities.
r
Convalescence by temporary senescence fr
Homing
in on nuclear
export
BOGERD,
H. P., FRIDELL, R. A., BENSON, R. E. and CULLEN, B. R. (1996) Protein sequence requirements for function of the human T-cell leukemia virus type 1 Rex nuclear export signal delineated by a novel in viva randomization selection assay Mol. Cell. Biol. 16, 4207-4214 MEYER, 6. E., MEINKOTH, j. L. and MALIM, M. E. (1996) Nuclear transport of human immunodeficiency virus type 1, visna virus, and equine infectious anemia virus Rev proteins: identification of a family of transferable nuclear export signals
1. Virol. 70, 2350-2359 The identification of consensus sequences for nuclear import has played a major contribution in our understanding of nuclear transport. More recently, studies have focused on the identification of complimentary sequences for nuclear export, and two major types of nuclear-export signal (NES) have been found. The first is the M9 domain of the hnRNP Al protein, a relatively long (40 residue), glycinerich sequence. The second was identified in the Rev/Rex family proteins, which mediate nuclear export of retrovirus genomes, and in protein kinase inhibitor (PKI) a. In these NESS leucine and isoleucine residues are critical for function, but precise consensus sequences have not yet been delineated. Bogerd et al. define the amino acid requirements of the NES of the Rex protein from the pathogenic retrovirus human T-cell leukaemia virus type 1 (HTLV-1). Human immunodeficiency virus 1 (HIV-l) Rev and HTLV-1 Rex are closely related and bind to a nuclear receptor molecule (the Rev/Rex activation domain-binding protein, or Rab - not to be confused with the Rab family of small GTPases). The authors screened an array of different mutants of the Rex NES and monitored both interaction with Rab and nuclear trends
in CELL BIOLOGY
(Vol.
6) October
1996
WANG, X-Z. er al. (1996) Signals from the stressed endoplasmic reticulum C/EBP homologous protein (CHOP/GADD153)
induce
Mol. Cell. Biol. 16, 4273-4280 The transcriptional regulator GADDl53/CHOP had been isolated in two independent ways: as one of a subset of proteins induced by DNA damage whose expression also correlated with starvation-induced growth arrest, and as a dominant-negative inhibitor of the differentiationassociated family of transcription factors C/EBP. Unlike other growth regulators, CHOP appeared to inhibit proliferation, but without promoting differentiation. This apparent paradox may now be solved: the data of Wang and colleagues show that the apparent induction of CHOP expression in response to starvation or DNA damage is in fact due to a response to a different type of cellular stress: the presence of improperly folded proteins in the endoplasmic reticulum (ER). This pathway, called the unfolded-protein response (UPR), involves the transcriptional upregulation of chaperones such as BiP. In vivo, the UPR can be induced by various means, such as glucose starvation or treatment of cells with tunicamycin, both of which inhibit protein glycosylation. Wang et al. show clearly that CHOP is also induced by these treatments and, conversely, that those treatments that had been shown previously to induce CHOP (namely DNA damage and glucose starvation) also induce the UPR. Furthermore, in cells overexpressing BiP, the induction of the UPR by tunicamycin and by DNA damage is attenuated, as is the induction of CHOP, suggesting that the induction of CHOP is indeed correlated with activation of the UPR. Finally, even under conditions of DNA damage that lead to the activation of the tumour-suppressor protein ~53 or stress-activated protein kinases, CHOP is not consistently induced, showing that the DNA-damage response and the UPR are independent. Stress often has unexpected effects, and, while these data remove CHOP from one pathway, this protein may still be at the centre of a response serving to prevent sick cells from embarking on challenging paths, such as growth or differentiation, until health returns.
379