Cross‐species divergence of the major recognition pathways of ubiquitylated substrates for ubiquitin/26<i>S</i> proteasome‐mediated proteolysis

Fatimababy, Antony S.; Lin, Yaling; Usharani, Raju; Radjacommare, R.; Wang, Hsing-Ting; Tsai, Huang-Lung; Lee, Yenfen; Fu, Hongyong

doi:10.1111/j.1742-4658.2009.07531.x

Cited by 44 publications

(76 citation statements)

References 41 publications

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“…S5a/PSMD4/Rpn10 and ADRM1/Rpn13 are intrinsic subunits of the 19S RP that bind ubiquitin and are involved in substrate recognition. 10, 11, 12, 13 There is evidence for additional ubiquitin-binding activity in the 19S RP. 14, 15 A substantial proportion of S5a is extraproteasomal.…”

Section: Introductionmentioning

confidence: 99%

The degradation of p53 and its major E3 ligase Mdm2 is differentially dependent on the proteasomal ubiquitin receptor S5a

et al. 2013

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p53 and its major E3 ligase Mdm2 are both ubiquitinated and targeted to the proteasome for degradation. Despite the importance of this in regulating the p53 pathway, little is known about the mechanisms of proteasomal recognition of ubiquitinated p53 and Mdm2. In this study, we show that knockdown of the proteasomal ubiquitin receptor S5a/PSMD4/Rpn10 inhibits p53 protein degradation and results in the accumulation of ubiquitinated p53. Overexpression of a dominant-negative deletion of S5a lacking its ubiquitin-interacting motifs (UIM)s, but which can be incorporated into the proteasome, also causes the stabilization of p53. Furthermore, small-interferring RNA (siRNA) rescue experiments confirm that the UIMs of S5a are required for the maintenance of low p53 levels. These observations indicate that S5a participates in the recognition of ubiquitinated p53 by the proteasome. In contrast, targeting S5a has no effect on the rate of degradation of Mdm2, indicating that proteasomal recognition of Mdm2 can be mediated by an S5a-independent pathway. S5a knockdown results in an increase in the transcriptional activity of p53. The selective stabilization of p53 and not Mdm2 provides a mechanism for p53 activation. Depletion of S5a causes a p53-dependent decrease in cell proliferation, demonstrating that p53 can have a dominant role in the response to targeting S5a. This study provides evidence for alternative pathways of proteasomal recognition of p53 and Mdm2. Differences in recognition by the proteasome could provide a means to modulate the relative stability of p53 and Mdm2 in response to cellular signals. In addition, they could be exploited for p53-activating therapies. This work shows that the degradation of proteins by the proteasome can be selectively dependent on S5a in human cells, and that this selectivity can extend to an E3 ubiquitin ligase and its substrate.

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Section: Introductionmentioning

confidence: 99%

The degradation of p53 and its major E3 ligase Mdm2 is differentially dependent on the proteasomal ubiquitin receptor S5a

et al. 2013

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“…As examples, Lys-48 and Lys-11-linked chains commit proteins to degradation, while Lys-63 linked chains direct nonproteolytic outcomes related to DNA repair and endocytosis (Komander and Rape, 2012). The bound Ubs are then recognized by over 16 structurally distinct Ub recognition motifs, depending on the process (Harper and Schulman, 2006;Fatimababy et al, 2010). Numerous DUBs also exist to reverse ubiquitylation, with as many as 70 identified thus far in Arabidopsis (Yan et al, 2000;Vierstra, 2009).…”

Section: Ub and Its Central Role In Protein Turnovermentioning

confidence: 99%

“…To prevent inadvertent release by deconjugases, these UBL domains lack the C-terminal Gly. Members of the UBL-UBA family are uniquely organized in having an N-terminal UBL domain followed by one or more UBA domains that recognize Ub (Farmer et al, 2010;Fatimababy et al, 2010). By simultaneously binding ubiquitylated proteins via the UBA domain and the proteasomal receptors RPN1, RPN10, or RPN13 through the UBL domain, these proteins chaperone Ub targets to the 26S complex for turnover .…”

Section: Ubl Domain Fusionsmentioning

confidence: 99%

The Expanding Universe of Ubiquitin and Ubiquitin-Like Modifiers

2012

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As we near a complete understanding of plant tran-scriptomes and their corresponding proteomes, a remaining frontier in plant biology will be the in-depth definition of the posttranslational modifications that help generate the diverse array of appropriately functioning proteins from more finite genomic information. It is now obvious that plant proteins are subject to a wide array of possible modifications that regulate their structure, activity, interactions, location, and/or half-life. These alterations are often genetically predetermined, transient , and highly dynamic, thus providing near unlimited layers of control across the life span of individual proteins. The continually expanding list of over 200 possibilities include the covalent addition of methyl, acetyl, phosphate, and glycosyl moieties, fatty acids, vitamin cofactors, nucleosides, and even other proteins. The first polypeptide modifier to be discovered was ubiquitin (Ub), a highly conserved, 76-amino acid protein ubiquitously present in eukaryotes (Hershko and Ciechanover, 1998; Smalle and Vierstra, 2004; Vierstra, 2009). Via an intricate enzymatic cascade, Ub becomes attached to a multitude of targets through an isopeptide bond between its C-terminal Gly residue and one or more accessible Lys residues in its targets. This addition can then be reversed by a family of deubiquitylating proteases (DUBs) that uniquely recognize and cleave the bond linking the two moieties, thus generating a reaction cycle akin to those involving protein kinases and phosphatases. Elucidation of the Ub enzymatic paradigm was followed by the discovery that it represents just one member from a constellation of peptide tags that become reversibly attached to other intracellular constituents , including lipids and prenyl groups, in some cases using parallel chemistries indicative of a common ancestor (Downes and Vierstra, 2005; Kerscher et al., 2006; Burroughs et al., 2012). In plants, these Ub-like modifiers (UBLs) currently include RUB (for related to ubiquitin, or Nedd8 in yeast [Saccharomyces cerevisiae] and animals), SUMO (for small ubiquitin-like modifier), ATG8 (for autophagy8) and ATG12, MUB (for membrane-anchored ubiquitin-fold protein), UFM1 (for ubiquitin-fold modifier1), URM1 (for ubiquitin-related modifier1), HUB1 (for homology to ubiquitin1), and a diverse assortment of proteins that harbor structurally related folds fused translationally to other domains. The varied processes managed by these modifiers are extraordinary , ranging from cellular housekeeping, nutrient recycling, and sulfur chemistry to selective protein turnover, transcriptional regulation, chromatin re-modeling, and RNA metabolism (Miura et al., 2007a; Hochstrasser, 2009; Vierstra, 2009; Li and Vierstra, 2012). In this review, I provide a glimpse into the importance of these modifiers in plant biology, an emerging appreciation for how these modifiers intersect to expand their influence, and how they might have evolved from prokaryotic progenitors. Specific examples supporting these themes are ...

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“…The rpn10-1 allele expresses a truncation of RPN10, the main Ub receptor in the 26S complex, and has much stronger developmental consequences (Smalle et al, 2003). The translated polypeptide includes the N-terminal von Willebrand Factor-A domain that links RPN10 to the rest of the RP but is missing the C-terminal region containing the three Ub-interacting motifs that bind Ub, the autophagy adaptor ATG8, and cargo receptors bearing Ub-like domains, respectively (Farmer et al, 2010;Fatimababy et al, 2010;Marshall et al, 2015).…”

Section: S Proteasome Subunits Are Upregulated During Proteotoxic Smentioning

confidence: 99%

The Proteasome Stress Regulon Is Controlled by a Pair of NAC Transcription Factors in Arabidopsis

et al. 2016

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Proteotoxic stress, which is generated by the accumulation of unfolded or aberrant proteins due to environmental or cellular perturbations, can be mitigated by several mechanisms, including activation of the unfolded protein response and coordinated increases in protein chaperones and activities that direct proteolysis, such as the 26S proteasome. Using RNA-seq analyses combined with chemical inhibitors or mutants that induce proteotoxic stress by impairing 26S proteasome capacity, we defined the transcriptional network that responds to this stress in Arabidopsis thaliana. This network includes genes encoding core and assembly factors needed to build the complete 26S particle, alternative proteasome capping factors, enzymes involved in protein ubiquitylation/deubiquitylation and cellular detoxification, protein chaperones, autophagy components, and various transcriptional regulators. Many loci in this proteasome-stress regulon contain a consensus cis-element upstream of the transcription start site, which was previously identified as a binding site for the NAM/ATAF1/CUC2 78 (NAC78) transcription factor. Double mutants disrupting NAC78 and its closest relative NAC53 are compromised in the activation of this regulon and notably are strongly hypersensitive to the proteasome inhibitors MG132 and bortezomib. Given that NAC53 and NAC78 homo-and heterodimerize, we propose that they work as a pair in activating the expression of numerous factors that help plants survive proteotoxic stress and thus play a central regulatory role in maintaining protein homeostasis.

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Cross‐species divergence of the major recognition pathways of ubiquitylated substrates for ubiquitin/26S proteasome‐mediated proteolysis

Cited by 44 publications

References 41 publications

The degradation of p53 and its major E3 ligase Mdm2 is differentially dependent on the proteasomal ubiquitin receptor S5a

The degradation of p53 and its major E3 ligase Mdm2 is differentially dependent on the proteasomal ubiquitin receptor S5a

The Expanding Universe of Ubiquitin and Ubiquitin-Like Modifiers

The Proteasome Stress Regulon Is Controlled by a Pair of NAC Transcription Factors in Arabidopsis

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