How the proteasome is degraded

Hoeller, Daniela; Đikić, Ivan

doi:10.1073/pnas.1616535113

Cited by 17 publications

(9 citation statements)

References 20 publications

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“…This study is also in harmony with another observation which identified that Siah2 could regulate the cellular pool of its kinases through ubiquitination [40]. Most of the ubiquitinated proteins are targeted for proteasomal degradation [41,42] and our results also point towards the proteasomal degradation of MRCKβ in H. pylori-infected GECs. Although there is no report on the status and role of MRCKβ in GC, our finding is supported by the human protein atlas information on "stomach cancer" showing that only 16.67% GC samples moderately express Cdc42BPB (MRCKβ) and the rest do not stain for the protein (v19.proteinatlas.…”

Section: Discussionsupporting

confidence: 91%

Helicobacter pylori-induced gastric cancer is orchestrated by MRCKβ-mediated Siah2 phosphorylation

et al. 2021

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Background Helicobacter pylori-mediated gastric carcinogenesis is initiated by a plethora of signaling events in the infected gastric epithelial cells (GECs). The E3 ubiquitin ligase seven in absentia homolog 2 (Siah2) is induced in GECs in response to H. pylori infection. Posttranslational modifications of Siah2 orchestrate its function as well as stability. The aim of this study was to evaluate Siah2 phosphorylation status under the influence of H. pylori infection and its impact in gastric cancer progression. Methods H. pylori-infected various GECs, gastric tissues from H. pylori-infected GC patients and H. felis-infected C57BL/6 mice were evaluated for Siah2 phosphorylation by western blotting or immunofluorescence microscopy. Coimmunoprecipitation assay followed by mass spectrometry were performed to identify the kinases interacting with Siah2. Phosphorylation sites of Siah2 were identified by using various plasmid constructs generated by site-directed mutagenesis. Proteasome inhibitor MG132 was used to investigate proteasome degradation events. The importance of Siah2 phosphorylation on tumorigenicity of infected cells were detected by using phosphorylation-null mutant and wild type Siah2 stably-transfected cells followed by clonogenicity assay, cell proliferation assay, anchorage-independent growth and transwell invasion assay. Results Siah2 was phosphorylated in H. pylori-infected GECs as well as in metastatic GC tissues at residues serine6 (Ser6) and threonine279 (Thr279). Phosphorylation of Siah2 was mediated by MRCKβ, a Ser/Thr protein kinase. MRCKβ was consistently expressed in uninfected GECs and noncancer gastric tissues but its level decreased in infected GECs as well as in metastatic tissues which had enhanced Siah2 expression. Infected murine gastric tissues showed similar results. MRCKβ could phosphorylate Siah2 but itself got ubiquitinated from this interaction leading to the proteasomal degradation of MRCKβ and use of proteasomal inhibitor MG132 could rescue MRCKβ from Siah2-mediated degradation. Ser6 and Thr279 phosphorylated-Siah2 was more stable and tumorigenic than its non-phosphorylated counterpart as revealed by the proliferation, invasion, migration abilities and anchorage-independent growth of stable-transfected cells. Conclusions Increased level of Ser6 and Thr279-phosphorylated-Siah2 and downregulated MRCKβ were prominent histological characteristics of Helicobacter-infected gastric epithelium and metastatic human GC. MRCKβ-dependent Siah2 phosphorylation stabilized Siah2 which promoted anchorage-independent survival and proliferative potential of GECs. Phospho-null mutants of Siah2 (S6A and T279A) showed abated tumorigenicity.

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Section: Discussionsupporting

confidence: 91%

Helicobacter pylori-induced gastric cancer is orchestrated by MRCKβ-mediated Siah2 phosphorylation

et al. 2021

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“…The 19S particle Rpn1, Rpn10 and Rpn13 of the lid sub-complex act either directly [ 8 ]. via their own ubiquitin-binding domains (UBDs) or indirectly via the UBDs of shuttling proteins, such as p62 or Rad23 [ 9 ]. Deubiquitylation of incoming substrates is carried out by the deubiquitylating enzymes (DUBs) Rpn11, Uch37, and Ubp6/Usp14 [ 10 ].…”

Section: Proteasome Plasticitymentioning

confidence: 99%

Adaptation of Proteasomes and Lysosomes to Cellular Environments

Mebratu

Negasi

Dutta

et al. 2020

Cells

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Protein degradation is important for proper cellular physiology as it removes malfunctioning proteins or can provide a source for energy. Proteasomes and lysosomes, through the regulatory particles or adaptor proteins, respectively, recognize proteins destined for degradation. These systems have developed mechanisms to allow adaptation to the everchanging environment of the cell. While the complex recognition of proteins to be degraded is somewhat understood, the mechanisms that help switch the proteasomal regulatory particles or lysosomal adaptor proteins to adjust to the changing landscape of degrons, during infections or inflammation, still need extensive exploration. Therefore, this review is focused on describing the protein degradation systems and the possible sensors that may trigger the rapid adaptation of the protein degradation machinery.

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“…As in previous analyses, we compared the mitochondrial protein findings to data from another target of autophagy [56]. Because ribosomal turnover showed little dependence on autophagy in the fibroblasts, we compared mitochondrial proteins from fibroblasts and fly heads to proteins of the proteasome, which also undergoes autophagic degradation [57]. The range of autophagy-dependent turnover rates was much larger for mitochondrial than for proteasomal proteins in both ATG7 −/− and ATG5 −/− fibroblasts, and in Atg7 null fly heads as well ( Figure 5(c)).…”

Section: Autophagy-dependent Turnover Rates Of Mitochondrial Proteinsmentioning

confidence: 99%

Autophagy accounts for approximately one-third of mitochondrial protein turnover and is protein selective

et al. 2019

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The destruction of mitochondria through macroautophagy (autophagy) has been recognised as a major route of mitochondrial protein degradation since its discovery more than 50 years ago, but fundamental questions remain unanswered. First, how much mitochondrial protein turnover occurs through autophagy? Mitochondrial proteins are also degraded by nonautophagic mechanisms, and the proportion of mitochondrial protein turnover that occurs through autophagy is still unknown. Second, does autophagy degrade mitochondrial proteins uniformly or selectively? Autophagy was originally thought to degrade all mitochondrial proteins at the same rate, but recent work suggests that mitochondrial autophagy may be protein selective. To investigate these questions, we used a proteomics-based approach in the fruit fly Drosophila melanogaster, comparing mitochondrial protein turnover rates in autophagy-deficient Atg7 mutants and controls. We found that~35% of mitochondrial protein turnover occurred via autophagy. Similar analyses using parkin mutants revealed that parkin-dependent mitophagy accounted for~25% of mitochondrial protein turnover, suggesting that most mitochondrial autophagy specifically eliminates dysfunctional mitochondria. We also found that our results were incompatible with uniform autophagic turnover of mitochondrial proteins and consistent with proteinselective autophagy. In particular, the autophagic turnover rates of individual mitochondrial proteins varied widely, and only a small amount of the variation could be attributed to tissue differences in mitochondrial composition and autophagy rate. Furthermore, analyses comparing autophagy-deficient and control human fibroblasts revealed diverse autophagy-dependent turnover rates even in homogeneous cells. In summary, our work indicates that autophagy acts selectively on mitochondrial proteins, and that most mitochondrial protein turnover occurs through non-autophagic processes.

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How the proteasome is degraded

Cited by 17 publications

References 20 publications

Helicobacter pylori-induced gastric cancer is orchestrated by MRCKβ-mediated Siah2 phosphorylation

Helicobacter pylori-induced gastric cancer is orchestrated by MRCKβ-mediated Siah2 phosphorylation

Adaptation of Proteasomes and Lysosomes to Cellular Environments

Autophagy accounts for approximately one-third of mitochondrial protein turnover and is protein selective

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