The Lhs1/GRP170 Chaperones Facilitate the Endoplasmic Reticulum-associated Degradation of the Epithelial Sodium Channel

Buck, Teresa M.; Plavchak, Lindsay; Roy, Ankita; Donnelly, Bridget F.; Kashlan, Ossama B.; Kleyman, Thomas R.; Subramanya, Arohan R.; Brodsky, Jeffrey L.

doi:10.1074/jbc.m113.469882

Cited by 48 publications

(74 citation statements)

References 114 publications

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“…Their data indicated that Hsp40 proteins, independently of Hsp70, might select substrates for ERAD, and that ENaC required unique molecular chaperones for ERAD. They also determined that the chaperone Lhs1/GRP170 (also known as HYOU1) selects the nonglycosylated form of the α-ENaC for ERAD (Buck et al, 2013). Our studies on the ENaC regulation by derlin-1 provide more evidence for ENaC as a substrate for an ERAD quality control system and contribute additional information regarding the pathways of ENaC degradation.…”

Section: Discussionmentioning

confidence: 67%

Derlin-1 promotes ubiquitylation and degradation of the epithelial Na+ channel, ENaC

You

Zhang

et al. 2017

Journal of Cell Science

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Ubiquitylation of the epithelial Na + channel (ENaC) plays a critical role in cellular functions, including transmembrane transport of Na + , Na + and water balance, and blood pressure stabilization. Published studies have suggested that ENaC subunits are targets of ER-related degradation (ERAD) in yeast systems. However, the molecular mechanism underlying proteasome-mediated degradation of ENaC subunits remains to be established. Derlin-1, an E3 ligase mediator, links recognized target proteins to ubiquitin-mediated proteasomal degradation in the cytosol. In the present study, we found that derlin-1 suppressed the expression of ENaC at the protein level and that the subunit α-ENaC (also known as SCNN1A) physically interacted with derlin-1 at the membrane-anchored domains or the loop regions, and that derlin-1 initiated α-ENaC retrotranslocation. In addition, HUWE1, an endoplasmic reticulum (ER)-resident E3 ubiquitin ligase, was recruited and promoted K11-linked polyubiquitylation of α-ENaC and, hence, formation of an α-ENaC ubiquitin-mediated degradation complex. These findings suggest that derlin-1 promotes ENaC ubiquitylation and enhances ENaC ubiquitinmediated proteasome degradation. The derlin-1 pathway therefore may represent a significant early checkpoint in the recognition and degradation of ENaC in mammalian cells.

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Section: Discussionmentioning

confidence: 67%

Derlin-1 promotes ubiquitylation and degradation of the epithelial Na+ channel, ENaC

You

Zhang

et al. 2017

Journal of Cell Science

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“…For example, in yeast, the ER lumen-resident heat shock protein (Hsp)70-related Lhs1 selectively targets the ␣-subunit for ER-associated degradation but does not affect the degrada- tion of the ␤-or ␥-subunit (9). Its mammalian homolog, Grp170, also enhances ␣-subunit turnover in human embryonic kidney cells (9). In contrast, luminal Hsp40s enhance the degradation of all three subunits in yeast (8).…”

Section: Discussionmentioning

confidence: 99%

Deletion of α-subunit exon 11 of the epithelial Na⁺ channel reveals a regulatory module

Chen

Kleyman

Sheng

2014

American Journal of Physiology-Renal Physiology

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“…Biochemical and structural analyses of the yeast Sil1-Kar2p complex (42) indicate that Sil1 binding to ADP-Kar2p triggers a conformational change in Kar2p that releases ADP; whether this binding reaction is sufficient to induce substrate release from Kar2p, or requires subsequent ATP binding, is not clear. Note that deletion of SIL1 (21) but not LHS1 (39) resulted in a moderate ERAD phenotype, suggesting that Sil1 may exert a potential role in ERAD in yeast.…”

Section: Discussionmentioning

confidence: 99%

“…In fact, Grp170's holdase but not NEF activity was implicated in ERAD in mammalian cells (39). In contrast, in part because it is not an ATPase, Sil1's NEF activity likely operates differently from that of Grp170.…”

Section: Discussionmentioning

confidence: 99%

“…Interestingly, this holdase but not NEF activity was recently implicated in ERAD of the epithelial sodium channel ␣ subunit, a BiP-independent ERAD substrate (39). Although recombinant Grp170-FLAG promoted release of the ER-localized SV40 from BiP in a nucleotide-dependent manner in vitro, whether Grp170 promotes SV40 infection by using its inherent nucleotide exchange or holdase activities in cells is unclear.…”

Section: Release Of Bip From Sv40 Promotes Viral Membrane Binding In mentioning

confidence: 99%

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A Nucleotide Exchange Factor Promotes Endoplasmic Reticulum-to-Cytosol Membrane Penetration of the Nonenveloped Virus Simian Virus 40

Inoue

Tsai

2015

J Virol

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The nonenveloped simian polyomavirus (PyV) simian virus 40 (SV40) hijacks the endoplasmic reticulum (ER) quality control machinery to penetrate the ER membrane and reach the cytosol, a critical infection step. During entry, SV40 traffics to the ER, where host-induced conformational changes render the virus hydrophobic. The hydrophobic virus binds and integrates into the ER lipid bilayer to initiate membrane penetration. However, prior to membrane transport, the hydrophobic SV40 recruits the ER-resident Hsp70 BiP, which holds the virus in a transport-competent state until it is ready to cross the ER membrane. Here we probed how BiP disengages from SV40 to enable the virus to penetrate the ER membrane. We found that nucleotide exchange factor (NEF) Grp170 induces nucleotide exchange of BiP and releases SV40 from BiP. Importantly, this reaction promotes SV40 ER-to-cytosol transport and infection. The human BK PyV also relies on Grp170 for successful infection. Interestingly, SV40 mobilizes a pool of Grp170 into discrete puncta in the ER called foci. These foci, postulated to represent the ER membrane penetration site, harbor ER components, including BiP, known to facilitate viral ER-to-cytosol transport. Our results thus identify a nucleotide exchange activity essential for catalyzing the most proximal event before ER membrane penetration of PyVs. IMPORTANCEPyVs are known to cause debilitating human diseases. During entry, this virus family, including monkey SV40 and human BK PyV, hijacks ER protein quality control machinery to breach the ER membrane and access the cytosol, a decisive infection step. In this study, we pinpointed an ER-resident factor that executes a crucial role in promoting ER-to-cytosol membrane penetration of PyVs. Identifying a host factor that facilitates entry of the PyV family thus provides additional therapeutic targets to combat PyV-induced diseases. Pathogens hijack protein quality control pathways of host cells to successfully cause infection. One pathway co-opted by pathogens during entry is endoplasmic reticulum (ER)-associated degradation (ERAD) (1-3). While ERAD is a surveillance system normally dedicated to the removal of misfolded ER proteins to the cytosol for proteasomal destruction, pathogens can co-opt elements of this pathway to gain entry into the host cytosol by disguising themselves as misfolded ER proteins. A clearer picture of the nature of this pathogen-host interaction is slowly emerging.Entry of the nonenveloped polyomavirus (PyV) family, including the simian virus 40 (SV40) and the human BK PyVs, serves as a salient example of pathogens that co-opt the ERAD pathway during infection (4-6). Structurally, SV40 is composed of 360 copies of the VP1 major coat protein arranged as 72 pentamers, with each pentamer engaging either the VP2 or VP3 internal hydrophobic minor coat protein. The pentamers are assembled as a 45-nm-diameter icosahedral particle that in turn encapsulates its viral DNA genome (7,8). To infect cells, SV40 undergoes receptor-mediated endocytosis a...

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The Lhs1/GRP170 Chaperones Facilitate the Endoplasmic Reticulum-associated Degradation of the Epithelial Sodium Channel

Cited by 48 publications

References 114 publications

Derlin-1 promotes ubiquitylation and degradation of the epithelial Na+ channel, ENaC

Derlin-1 promotes ubiquitylation and degradation of the epithelial Na+ channel, ENaC

Deletion of α-subunit exon 11 of the epithelial Na⁺ channel reveals a regulatory module

A Nucleotide Exchange Factor Promotes Endoplasmic Reticulum-to-Cytosol Membrane Penetration of the Nonenveloped Virus Simian Virus 40

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The Lhs1/GRP170 Chaperones Facilitate the Endoplasmic Reticulum-associated Degradation of the Epithelial Sodium Channel

Cited by 48 publications

References 114 publications

Derlin-1 promotes ubiquitylation and degradation of the epithelial Na+ channel, ENaC

Derlin-1 promotes ubiquitylation and degradation of the epithelial Na+ channel, ENaC

Deletion of α-subunit exon 11 of the epithelial Na+ channel reveals a regulatory module

A Nucleotide Exchange Factor Promotes Endoplasmic Reticulum-to-Cytosol Membrane Penetration of the Nonenveloped Virus Simian Virus 40

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Deletion of α-subunit exon 11 of the epithelial Na⁺ channel reveals a regulatory module