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Editorial overview
Post-transcriptional Editorial Don W. Cleveland
processes
overview
and Alan C. Hinnebusch
Johns Hopkins University School of Medicine, Baltimore and National Institutes of Health, Bethesda, Maryland, USA Current Opinion in Cell Biology 1992, 4:973-974 Introduction
By tradition, the topic we cover in this section in the final issue of the 1992 Current Opinion in Cell Biology is named post-transcriptional processes. However, as nuclear RNA transport [ 1] and RNA editing [2] were covered last year, and RNA splicing [3] has already been discussed in an earlier issue, due to the divisions in the bibliographic literature, perhaps ‘post-nuclear processes’ would fit this year’s topics more precisely. Even this narrower definition leaves an area so vast that any coverage will by necessity omit large subject areas and the aggregate of those that are covered yields a somewhat eclectic feel. What (we hope) distinguishes the areas that are included in this issue is that recent progress has made each topic of general interest to a broad cell biological audience. We have organized the nine reviews in an order that reflects, at least loosely, their normal temporal progression in the cell. First covered are questions involving mRNA localization and stability, both of which play key roles in establishing where and how much of a specific protein is synthesized. Second comes examination of how the folding of newly made polypeptides is catalyzed by cytoplasmic chaperones. Third, a set of four reviews summarizes what we know of the mechanisms that lead to (and biological functions of) the ever increasing number of protein modifications, including phosphorylation, dephosphorylation, prenylation and glycosylation. Finally, returning to controlling the abundance of polypeptide products, a pair of reviews cover divergent aspects of protein degradation, focusing either on the ubiquitinlinked degradation pathway or on newly discovered proteases with unexpected specificities that include recognition of secondary structure.
Controlling
mRNA localization
and stability
In the first review, Kislauskis and Singer (pp 975-978) cover the known examples of specific mRNAs that are not found ubiquitously throughout the cytoplasm, but rather are targeted to discrete locations. As they recount, it is now clear that localized ENAs are used abundantly to direct local protein synthesis during early development (demonstrated thus far in Drasophih and Xeno pus). An emerging consensus is that localization involves @ Current
Biology
‘zip code’ nucleic acid sequences that lie within the 3’ untranslated regions of the mRNAs. Some of this information is apparently used within the nucleus to direct RNA export in a polarized fashion; in other cases, these ‘zip code’ determinants may specify retention in one or more cytoplasmic compartments. Next, we return to a topic covered last year: the pathway of cytoplasmic mRNA degradation [4]. Overshadowed all to frequently by examination of transcriptional events, RNA stability plays a major role in regulating the level of gene expression. Excluding contributions from altemative RNA splicing and RNA transport, gene transcription and RNA half life play equivalent quantitative roles in establishing the steady state level of an mRNA Pelts and Jacobson (pp 979-983) detail the abundant progress that has been made during the past year in identification of components that participate in several instability pathways.
Protein
folding
As to the mechanisms and regulation of protein translation per se, we do not include a new look here, and instead refer readers to last year’s reviews by Rhoads [5] and Weiss [6]. Instead, we have recruited an up to the minute account from Kelley and Georgopoulos (pp 984-991) of how (and which) cytoplasmic chaperones are involved both co- and post-translationally in the folding, oligomerization and/or disassembly of protein subunits and complexes. Despite the conformational changes that chaperones cause, the enduring unifying property of this burgeoning population of proteins is the lack of overall covalent modification by the chaperone and the exclusion of the chaperone from the finished product. The pace of these discoveries is blinding: earlier considerations of de nova protein folding in the absence of chaperones now seem something akin to looking at catalytic mechanisms without enzymes.
Protein
modification
Irrespective of the folding pathway is the repertoire of post-translational modifications to which proteins are Ltd ISSN 0955AM74
973
974
Post-transcrbtional
Drocesses
subjected. To last year’s coverage of mitogen-activated protein kinases [7], Ahn, Seger and Krebs (pp 992-999) now review the next level in this kinase cascade, i.e. a newly found kinase activator of the mitogen-activated protein kinase. Coming on the heels of a three decade long quest for kinases and phosphatases by Krebs and his long-time colleague Fischer, we cannot resist the opportunity to note that this contribution is among the first from Krebs since he and Fischer were awarded the 1992 Nobel Prize in Medicine. Of course, extending beyond addition of phosphates, it is obvious that signal transduction through kinase cascades implicitly assumes a flip side: phosphatases. As Pallen, Tan and Guy (pp 1000-1007) detail for several now well characterized phosphatases, there is increasing evidence that the regulated removal of phosphate groups from proteins is as important a step as their addition, particularly for signal attenuation. No additional post-translational modifications considered at length are protein prenylation and glycosylation. To the former, Cox and Der (pp lOO8-1016) describe the signals for prenylation, the properties of prenyl transferase enzymes, and the role of prenylation in the membrane interactions of prenylated proteins. To the latter, Hart (pp 1017-1023) charts the complicated course of intracellular and extracellular glycosylation. The rampant, O-linked, intracellular glycosylation of many nuclear and cytoplasmic proteins discovered by Hart and colleagues half a decade ago is found to be structurally simple, abundant and highly dynamic. This is in contrast with complex sugar moieties and extracellular glycosylation, which is often cell-type specific.
Protein
in some cases can target substrates via interaction with other proteins that are not degraded (referred to as trans-targeting). In the second, Resnick and Zasloff (pp 1032-1036) catalogue the properties of an emerging class of proteases of unusual and unexpected specificities. For example, in this group is the endopeptidase magaininase, which recognizes an amphipathic u-helix. This enzyme thus recognizes its substrates not through primary sequence, but rather through a secondary structural domain. Similarly, a novel plasma membrane bound-protease has been discovered that cleaves membrane-bound, a-helical substrates (such as the amyloid precursor protein whose aberrant cleavage products correlate with Alzheimer’s disease) not at a specific sequence, but at a defined distance from the membrane.
References 1.
MAQIJA~ LE: Nuclear 3:1004-1012.
2.
SOLINER-WEBB 3:10561061.
3.
RIO DC: 4:444-452.
4.
HIGGINS
Cell Biol 5. 6. 7.
RNA
mRNA
B:
RNA
Export.
Editing.
Processing.
Opin
Czrrr
Curr
Opin
CF: Stability and Degradation 1991, 3:1013-1018.
RHOADS RE: Protein sis. Curr Opin Cell
Biol 1991,
Synthesis:
WEISS RB: Rihosomal through. Cwr Opin
Cell Biol
Opin
Cwr
Cell
Rio/
1991,
Cell
Biol
1992,
of mRNA
Cwr
Opin
Cell Growth 3:1019-1924.
Frameshifting, 1991,
Cell Rio/ 1991,
and
Jumping 3:1051-1054.
Oncogene-
and
Read-
COHB MH. ROBBINS DJ, BOLJLTON TG: ERKs, Extracellular Signal-regulated W-2 Kinases. Cm-r Opin Cell Biol 1991, 3:1025-1032.
degradation
Completing our look at post-transcriptional processes are two aspects of post-translational protein degradation. In the first, Hochstrasser (pp 1024-1031) focuses on the ATP-dependent ubiquitin system, in which degradation is mediated through covalent linkage to the 76 amino acid ubiquitin polypeptide. The requisite specificity of degradation is achieved by controlling substrate selection that
DW Cleveland, Department Clniversit) School of Medicine, land 21205, USA
of Biological Chemistry, 725 North Wolfe Street,
AG Hinnebusch, Iaboraroly of Molecular Child Health and Human Development, Bethesda, Maryland 20892, USA
Genetics, National
Johns Hopkins Baltimore, May
National Institutes
Institute of of Health,
processes
overview
and Alan C. Hinnebusch
Johns Hopkins University School of Medicine, Baltimore and National Institutes of Health, Bethesda, Maryland, USA Current Opinion in Cell Biology 1992, 4:973-974 Introduction
By tradition, the topic we cover in this section in the final issue of the 1992 Current Opinion in Cell Biology is named post-transcriptional processes. However, as nuclear RNA transport [ 1] and RNA editing [2] were covered last year, and RNA splicing [3] has already been discussed in an earlier issue, due to the divisions in the bibliographic literature, perhaps ‘post-nuclear processes’ would fit this year’s topics more precisely. Even this narrower definition leaves an area so vast that any coverage will by necessity omit large subject areas and the aggregate of those that are covered yields a somewhat eclectic feel. What (we hope) distinguishes the areas that are included in this issue is that recent progress has made each topic of general interest to a broad cell biological audience. We have organized the nine reviews in an order that reflects, at least loosely, their normal temporal progression in the cell. First covered are questions involving mRNA localization and stability, both of which play key roles in establishing where and how much of a specific protein is synthesized. Second comes examination of how the folding of newly made polypeptides is catalyzed by cytoplasmic chaperones. Third, a set of four reviews summarizes what we know of the mechanisms that lead to (and biological functions of) the ever increasing number of protein modifications, including phosphorylation, dephosphorylation, prenylation and glycosylation. Finally, returning to controlling the abundance of polypeptide products, a pair of reviews cover divergent aspects of protein degradation, focusing either on the ubiquitinlinked degradation pathway or on newly discovered proteases with unexpected specificities that include recognition of secondary structure.
Controlling
mRNA localization
and stability
In the first review, Kislauskis and Singer (pp 975-978) cover the known examples of specific mRNAs that are not found ubiquitously throughout the cytoplasm, but rather are targeted to discrete locations. As they recount, it is now clear that localized ENAs are used abundantly to direct local protein synthesis during early development (demonstrated thus far in Drasophih and Xeno pus). An emerging consensus is that localization involves @ Current
Biology
‘zip code’ nucleic acid sequences that lie within the 3’ untranslated regions of the mRNAs. Some of this information is apparently used within the nucleus to direct RNA export in a polarized fashion; in other cases, these ‘zip code’ determinants may specify retention in one or more cytoplasmic compartments. Next, we return to a topic covered last year: the pathway of cytoplasmic mRNA degradation [4]. Overshadowed all to frequently by examination of transcriptional events, RNA stability plays a major role in regulating the level of gene expression. Excluding contributions from altemative RNA splicing and RNA transport, gene transcription and RNA half life play equivalent quantitative roles in establishing the steady state level of an mRNA Pelts and Jacobson (pp 979-983) detail the abundant progress that has been made during the past year in identification of components that participate in several instability pathways.
Protein
folding
As to the mechanisms and regulation of protein translation per se, we do not include a new look here, and instead refer readers to last year’s reviews by Rhoads [5] and Weiss [6]. Instead, we have recruited an up to the minute account from Kelley and Georgopoulos (pp 984-991) of how (and which) cytoplasmic chaperones are involved both co- and post-translationally in the folding, oligomerization and/or disassembly of protein subunits and complexes. Despite the conformational changes that chaperones cause, the enduring unifying property of this burgeoning population of proteins is the lack of overall covalent modification by the chaperone and the exclusion of the chaperone from the finished product. The pace of these discoveries is blinding: earlier considerations of de nova protein folding in the absence of chaperones now seem something akin to looking at catalytic mechanisms without enzymes.
Protein
modification
Irrespective of the folding pathway is the repertoire of post-translational modifications to which proteins are Ltd ISSN 0955AM74
973
974
Post-transcrbtional
Drocesses
subjected. To last year’s coverage of mitogen-activated protein kinases [7], Ahn, Seger and Krebs (pp 992-999) now review the next level in this kinase cascade, i.e. a newly found kinase activator of the mitogen-activated protein kinase. Coming on the heels of a three decade long quest for kinases and phosphatases by Krebs and his long-time colleague Fischer, we cannot resist the opportunity to note that this contribution is among the first from Krebs since he and Fischer were awarded the 1992 Nobel Prize in Medicine. Of course, extending beyond addition of phosphates, it is obvious that signal transduction through kinase cascades implicitly assumes a flip side: phosphatases. As Pallen, Tan and Guy (pp 1000-1007) detail for several now well characterized phosphatases, there is increasing evidence that the regulated removal of phosphate groups from proteins is as important a step as their addition, particularly for signal attenuation. No additional post-translational modifications considered at length are protein prenylation and glycosylation. To the former, Cox and Der (pp lOO8-1016) describe the signals for prenylation, the properties of prenyl transferase enzymes, and the role of prenylation in the membrane interactions of prenylated proteins. To the latter, Hart (pp 1017-1023) charts the complicated course of intracellular and extracellular glycosylation. The rampant, O-linked, intracellular glycosylation of many nuclear and cytoplasmic proteins discovered by Hart and colleagues half a decade ago is found to be structurally simple, abundant and highly dynamic. This is in contrast with complex sugar moieties and extracellular glycosylation, which is often cell-type specific.
Protein
in some cases can target substrates via interaction with other proteins that are not degraded (referred to as trans-targeting). In the second, Resnick and Zasloff (pp 1032-1036) catalogue the properties of an emerging class of proteases of unusual and unexpected specificities. For example, in this group is the endopeptidase magaininase, which recognizes an amphipathic u-helix. This enzyme thus recognizes its substrates not through primary sequence, but rather through a secondary structural domain. Similarly, a novel plasma membrane bound-protease has been discovered that cleaves membrane-bound, a-helical substrates (such as the amyloid precursor protein whose aberrant cleavage products correlate with Alzheimer’s disease) not at a specific sequence, but at a defined distance from the membrane.
References 1.
MAQIJA~ LE: Nuclear 3:1004-1012.
2.
SOLINER-WEBB 3:10561061.
3.
RIO DC: 4:444-452.
4.
HIGGINS
Cell Biol 5. 6. 7.
RNA
mRNA
B:
RNA
Export.
Editing.
Processing.
Opin
Czrrr
Curr
Opin
CF: Stability and Degradation 1991, 3:1013-1018.
RHOADS RE: Protein sis. Curr Opin Cell
Biol 1991,
Synthesis:
WEISS RB: Rihosomal through. Cwr Opin
Cell Biol
Opin
Cwr
Cell
Rio/
1991,
Cell
Biol
1992,
of mRNA
Cwr
Opin
Cell Growth 3:1019-1924.
Frameshifting, 1991,
Cell Rio/ 1991,
and
Jumping 3:1051-1054.
Oncogene-
and
Read-
COHB MH. ROBBINS DJ, BOLJLTON TG: ERKs, Extracellular Signal-regulated W-2 Kinases. Cm-r Opin Cell Biol 1991, 3:1025-1032.
degradation
Completing our look at post-transcriptional processes are two aspects of post-translational protein degradation. In the first, Hochstrasser (pp 1024-1031) focuses on the ATP-dependent ubiquitin system, in which degradation is mediated through covalent linkage to the 76 amino acid ubiquitin polypeptide. The requisite specificity of degradation is achieved by controlling substrate selection that
DW Cleveland, Department Clniversit) School of Medicine, land 21205, USA
of Biological Chemistry, 725 North Wolfe Street,
AG Hinnebusch, Iaboraroly of Molecular Child Health and Human Development, Bethesda, Maryland 20892, USA
Genetics, National
Johns Hopkins Baltimore, May
National Institutes
Institute of of Health,