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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
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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
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Post-transcrbtional
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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
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MAQIJA~ LE: Nuclear
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SOLINER-WEBB
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RIO DC:
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RHOADS RE: Protein
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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,