SGTA Recognizes a Noncanonical Ubiquitin-like Domain in the Bag6-Ubl4A-Trc35 Complex to Promote Endoplasmic Reticulum-Associated Degradation

Xu, Yue; Cai, Mengli; Yang, Yingying; Huang, Lan; Ye, Yihong

doi:10.1016/j.celrep.2012.11.010

Cited by 92 publications

(164 citation statements)

References 61 publications

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“…Because SGTA impacts the virus-Hsc70 interaction, we sought to determine whether SGTA's ability to associate with Hsc70 via SGTA's central TPR domain (Fig. 4A) (32-34), as well as SGTA's N-terminal domain, which mediates homodimerization and the recruitment cellular adapters, including the Ubl4A-Tric35-Bag6 complex (33)(34)(35)(36), is important during ER extraction and cytosol arrival of the virus. Since SGTA's C-terminal domain is limited to substrate binding (31,37,38) and unlikely to control Hsc70's function, we did not characterize this domain in this study.…”

Section: Resultsmentioning

confidence: 99%

SGTA-Dependent Regulation of Hsc70 Promotes Cytosol Entry of Simian Virus 40 from the Endoplasmic Reticulum

Dupzyk

Williams

Bagchi

et al. 2017

J Virol

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Membrane penetration by nonenveloped viruses remains enigmatic. In the case of the nonenveloped polyomavirus simian virus 40 (SV40), the virus penetrates the endoplasmic reticulum (ER) membrane to reach the cytosol and then traffics to the nucleus to cause infection. We previously demonstrated that the cytosolic Hsc70-SGTA-Hsp105 complex is tethered to the ER membrane, where Hsp105 and SGTA facilitate the extraction of SV40 from the ER and transport of the virus into the cytosol. We now find that Hsc70 also ejects SV40 from the ER into the cytosol in a step regulated by SGTA. Although SGTA's N-terminal domain, which mediates homodimerization and recruits cellular adaptors, is dispensable during ER-to-cytosol transport of SV40, this domain appears to exert an unexpected post-ER membrane translocation function during SV40 entry. Our study thus establishes a critical function of Hsc70 within the Hsc70-SGTA-Hsp105 complex in promoting SV40 ER-to-cytosol membrane penetration and unveils a role of SGTA in controlling this step.IMPORTANCE How a nonenveloped virus transports across a biological membrane to cause infection remains mysterious. One enigmatic step is whether host cytosolic components are co-opted to transport the viral particle into the cytosol. During ERto-cytosol membrane transport of the nonenveloped polyomavirus SV40, a decisive infection step, a cytosolic complex composed of Hsc70-SGTA-Hsp105 was previously shown to associate with the ER membrane. SGTA and Hsp105 have been shown to extract SV40 from the ER and transport the virus into the cytosol. We demonstrate here a critical role of Hsc70 in SV40 ER-to-cytosol penetration and reveal how SGTA controls Hsc70 to impact this process.KEYWORDS chaperones, endoplasmic reticulum, membrane transport, simian virus 40 T he molecular basis by which nonenveloped viruses penetrate biological membranes to gain entry into the host cytosol and cause infection remains mysterious (1). For enveloped viruses, fusion between the viral and a host membrane enables the core viral particle to reach the cytosol (2). However, since nonenveloped viruses lack a surrounding lipid bilayer, their membrane transport mechanisms are likely distinct from those of enveloped viruses. Although the precise molecular mechanism remains unclear, a general principle describing nonenveloped membrane translocation has nonetheless emerged. Upon trafficking to the site of membrane penetration, host cues, including cellular proteases, chaperones, reductases, and low pH, act on the viral particle to impart conformational changes. As a consequence, the conformationally altered virus becomes hydrophobic, enabling it to engage and disrupt the limiting membrane. Alternatively, the structural change may release a lytic peptide previously hidden in the native virus, which in turn integrates into and impairs the integrity of the membrane. Regardless of the mechanism, these reactions prime the viral (or subviral)

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Section: Resultsmentioning

confidence: 99%

SGTA-Dependent Regulation of Hsc70 Promotes Cytosol Entry of Simian Virus 40 from the Endoplasmic Reticulum

Dupzyk

Williams

Bagchi

et al. 2017

J Virol

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“…The TPR domain of Sgt2 is also involved in the homeostasis of other proteins (54,55). A recent study revealed that Sgt2 interacts with two key chaperones (Ssa1 and Hsp104) involved in prion pathogenesis and affects prion formation in yeast (56).…”

Section: Discussionmentioning

confidence: 99%

Structural and Functional Characterization of Ybr137wp Implicates Its Involvement in the Targeting of Tail-Anchored Proteins to Membranes

Yeh

Lin

et al. 2014

Molecular and Cellular Biology

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c Nearly 5% of membrane proteins are guided to nuclear, endoplasmic reticulum (ER), mitochondrial, Golgi, or peroxisome membranes by their C-terminal transmembrane domain and are classified as tail-anchored (TA) membrane proteins. In Saccharomyces cerevisiae, the guided entry of TA protein (GET) pathway has been shown to function in the delivery of TA proteins to the ER. The sorting complex for this pathway is comprised of Sgt2, Get4, and Get5 and facilitates the loading of nascent tail-anchored proteins onto the Get3 ATPase. Multiple pulldown assays also indicated that Ybr137wp associates with this complex in vivo. Here, we report a 2.8-Å-resolution crystal structure for Ybr137wp from Saccharomyces cerevisiae. The protein is a decamer in the crystal and also in solution, as observed by size exclusion chromatography and analytical ultracentrifugation. In addition, isothermal titration calorimetry indicated that the C-terminal acidic motif of Ybr137wp interacts with the tetratricopeptide repeat (TPR) domain of Sgt2. Moreover, an in vivo study demonstrated that Ybr137wp is induced in yeast exiting the log phase and ameliorates the defect of TA protein delivery and cell viability derived by the impaired GET system under starvation conditions. Therefore, this study suggests a possible role for Ybr137wp related to targeting of tail-anchored proteins.

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“…The Bag6 min fragment used in the study does not contain the Bag6 substrate-binding domain ( therefore, the Bag6 complex can promote the handoff of substrate from SGTA to TRC40 without Bag6 engaging the substrate directly. SGTA binds the Bag6 complex via the UBL domain of Ubl4A; consequently, the Bag6-dependent handoff should require this interaction (24,25). To test this hypothesis, the mutants hSGTA(C38A) and Ubl4A(L43A) were generated; previously, the equivalent mutations in yeast were shown to disrupt the homologous interaction (25).…”

Section: The Bag6 Min Complex Is An Independent Module That Facilitatmentioning

confidence: 99%

“…In yeast, these two proteins form a heterotetramer that regulates the handoff of the TA protein from the cochaperone small, glutamine-rich, tetratricopeptide repeat protein 2 (Sgt2) [small glutamine-rich tetratricopeptide repeat-containing protein (SGTA) in mammals] to the delivery factor Get3 (TRC40 in mammals) (19)(20)(21)(22). 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).…”

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confidence: 99%

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

Mock

Chartron

Zaslaver

et al. 2014

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

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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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SGTA Recognizes a Noncanonical Ubiquitin-like Domain in the Bag6-Ubl4A-Trc35 Complex to Promote Endoplasmic Reticulum-Associated Degradation

Cited by 92 publications

References 61 publications

SGTA-Dependent Regulation of Hsc70 Promotes Cytosol Entry of Simian Virus 40 from the Endoplasmic Reticulum

SGTA-Dependent Regulation of Hsc70 Promotes Cytosol Entry of Simian Virus 40 from the Endoplasmic Reticulum

Structural and Functional Characterization of Ybr137wp Implicates Its Involvement in the Targeting of Tail-Anchored Proteins to Membranes

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

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