Involvement of Bag6 and the TRC pathway in proteasome assembly

Akahane, Takashi; Sahara, Kazutaka; Yashiroda, Hideki; Tanaka, Keiji; Murata, Shigeo

doi:10.1038/ncomms3234

Cited by 31 publications

(31 citation statements)

References 44 publications

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“…Induction of PRB1 may reflect compensatory upregulation of vacuolar protein degradation, which may be necessary for the disposal of aberrant proteins and for maintenance of the amino acid pool required for cell survival under proteasome impairment [37]. In addition, we found that GET3, which participates in CP assembly [32], also contained PACE core in the promoter and was induced by Rpn4. This observation supports the importance of PACE core for proteasome assembly.…”

Section: -(A/ G/t)g(t/g)ggc(a/g)-3mentioning

confidence: 77%

Identification of minimum Rpn4‐responsive elements in genes related to proteasome functions

2015

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a b s t r a c tThe proteasome is an essential, 66-subunit protease that mediates ubiquitin-dependent proteolysis. The transcription factor Rpn4 regulates concerted expression of proteasome subunits to increase the proteasome by recognizing nonamer proteasome-associated control element (PACE) elements on the promoter regions. However, the genes for proteasome assembly chaperones and some of the subunits have no PACEs. Here we identified a minimal hexamer ''PACE-core'' sequence that responds to Rpn4. PACE-cores are found in many genes related to proteasome function including the assembly chaperones, but cannot substitute for PACE of the subunits. Our results add a new layer of complexity in transcriptional regulation of genes involved in protein degradation.

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Section: -(A/ G/t)g(t/g)ggc(a/g)-3mentioning

confidence: 77%

Identification of minimum Rpn4‐responsive elements in genes related to proteasome functions

2015

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“…It is expected that the mammalian homologs, along with Bag6, play a similar role (23)(24)(25)(26)(27). Bag6 also interacts with other proteins such as apoptosisinducing factor, glycoprotein 78 (gp78), regulatory particle 5, and brother of regulator of imprinted sites (BORIS) (16,(27)(28)(29)(30)(31)(32) and can homo-oligomerize, increasing the level of complexity (30). These findings build a picture of Bag6 as a central hub for a diverse physiological network of proteins.…”

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confidence: 95%

Bag6 complex contains a minimal tail-anchor–targeting module and a mock BAG domain

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et al. 2014

Proc. Natl. Acad. Sci. U.S.A.

129

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BCL2-associated athanogene cochaperone 6 (Bag6) plays a central role in cellular homeostasis in a diverse array of processes and is part of the heterotrimeric Bag6 complex, which also includes ubiquitin-like 4A (Ubl4A) and transmembrane domain recognition complex 35 (TRC35). This complex recently has been shown to be important in the TRC pathway, the mislocalized protein degradation pathway, and the endoplasmic reticulum-associated degradation pathway. Here we define the architecture of the Bag6 complex, demonstrating that both TRC35 and Ubl4A have distinct C-terminal binding sites on Bag6 defining a minimal Bag6 complex. A crystal structure of the Bag6–Ubl4A dimer demonstrates that Bag6–BAG is not a canonical BAG domain, and this finding is substantiated biochemically. Remarkably, the minimal Bag6 complex defined here facilitates tail-anchored substrate transfer from small glutamine-rich tetratricopeptide repeat-containing protein α to TRC40. These findings provide structural insight into the complex network of proteins coordinated by Bag6.

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“…Specifically, β subunits were poorly incorporated and this correlated with poor recruitment of CP assembly intermediates to the ER membrane. Strong genetic interactions between proteasome assembly factors and yeast components of the tail-anchoring pathway were also observed, suggesting a conserved mechanism involving CP assembly at ER membranes might be at play (Akahane et al 2013). The same study also reported that Bag6 was required for the stability of the Nas2 module as Bag6 knockdowns resulted in accumulation of RP-like species lacking Rpt4 and Rpt5 (Akahane et al 2013), suggesting Bag6 might have multiple roles in proteasome assembly.…”

Section: Localization In Assemblymentioning

confidence: 82%

“…Moreover, CP assembly defects were observed when TRC40 or Bag6, two proteins involved in the pathway which inserts tail-anchored proteins into the mammalian ER membrane, were knocked down (Akahane et al 2013). Specifically, β subunits were poorly incorporated and this correlated with poor recruitment of CP assembly intermediates to the ER membrane.…”

Section: Localization In Assemblymentioning

confidence: 99%

Putting it all together: intrinsic and extrinsic mechanisms governing proteasome biogenesis

2017

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BACKGROUND:The 26S proteasome is at the heart of the ubiquitin-proteasome system, which is the key cellular pathway for the regulated degradation of proteins and enforcement of protein quality control. The 26S proteasome is an unusually large and complicated protease comprising a 28-subunit core particle (CP) capped by one or two 19-subunit regulatory particles (RP). Multiple activities within the RP process incoming ubiquitinated substrates for eventual degradation by the barrel-shaped CP. The large size and elaborate architecture of the proteasome have made it an exceptional model for understanding mechanistic themes in macromolecular assembly. OBJECTIVE:In the present work, we highlight the most recent mechanistic insights into proteasome assembly, with particular emphasis on intrinsic and extrinsic factors regulating proteasome biogenesis. We also describe new and exciting questions arising about how proteasome assembly is regulated and deregulated in normal and diseased cells. METHODS:A comprehensive literature search using the PubMed search engine was performed, and key findings yielding mechanistic insight into proteasome assembly were included in this review. RESULTS:Key recent studies have revealed that proteasome biogenesis is dependent upon intrinsic features of the subunits themselves as well as extrinsic factors, many of which function as dedicated chaperones. CONCLUSION:Cells rely on a diverse set of mechanistic strategies to ensure the rapid, efficient, and faithful assembly of proteasomes from their cognate subunits. Importantly, physiological as well as pathological changes to proteasome assembly are emerging as exciting paradigms to alter protein degradation in vivo.

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Involvement of Bag6 and the TRC pathway in proteasome assembly

Cited by 31 publications

References 44 publications

Identification of minimum Rpn4‐responsive elements in genes related to proteasome functions

Identification of minimum Rpn4‐responsive elements in genes related to proteasome functions

Bag6 complex contains a minimal tail-anchor–targeting module and a mock BAG domain

Putting it all together: intrinsic and extrinsic mechanisms governing proteasome biogenesis

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