Regulated Erlin-dependent release of the B12 transmembrane J-protein promotes ER membrane penetration of a non-enveloped virus

Inoue, Takamitsu; Tsai, Billy

doi:10.1371/journal.ppat.1006439

Cited by 21 publications

(20 citation statements)

References 42 publications

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“…When the FLAG-tagged proteins were immunoprecipitated, endogenous Hsc70 was found in the WT B12-FLAG-but not the QPD B12-FLAG-precipitated sample (Fig. 1D, second row from top), indicating that WT B12, but not QPD B12, binds to Hsc70, as previously reported (31). Importantly, endogenous Bag2 was observed in the WT B12-FLAGprecipitated but minimally in the QPD B12-FLAG-precipitated material ( Fig.…”

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confidence: 83%

Bag2 Is a Component of a Cytosolic Extraction Machinery That Promotes Membrane Penetration of a Nonenveloped Virus

Dupzyk

Tsai

2018

J Virol

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During entry, the nonenveloped polyomavirus (PyV) simian virus 40 (SV40) traffics from the cell surface to the endoplasmic reticulum (ER), where it penetrates the ER membrane to reach the cytosol; the virus is then transported into the nucleus to cause infection. Although a coherent understanding of SV40's host entry is emerging, how the virus is ejected from the ER into the cytosol remains mysterious. Our previous analyses revealed that the cytosolic Hsc70-SGTA-Hsp105 complex binds to SV40 and extracts it from the ER into the cytosol. We now report that the nucleotide exchange factor (NEF) Bag2 stimulates SV40 release from Hsc70, thereby enabling successful virus arrival at the cytosol, which leads to infection. Hsp105, another NEF of Hsc70, displays a function overlapping that of Bag2, underscoring the importance of this release reaction. Our findings identify a new component of an extraction machinery essential during membrane penetration of a nonenveloped virus and provide further mechanistic insights into this process. How a nonenveloped virus penetrates a biological membrane to cause infection is a mystery. For the nonenveloped polyomavirus SV40, transport across the ER membrane to reach the cytosol is an essential virus infection step. Here, we identify a novel component of a cytosolic Hsc70-dependent chaperone complex called Bag2 that extracts SV40 from the ER into the cytosol. Bag2 does this by triggering SV40 release from Hsc70, thus ensuring that the virus reaches the cytosol for productive infection.

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supporting

confidence: 83%

Bag2 Is a Component of a Cytosolic Extraction Machinery That Promotes Membrane Penetration of a Nonenveloped Virus

Dupzyk

Tsai

2018

J Virol

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“…Importantly, in the same MS analysis, peptides corresponding to the ER membrane protein RTN4 were present in the 3xFLAG-B12 precipitated material, while peptides corresponding to RTN4 and RTN3 were identified in the 3xFLAG-C18 precipitated samples (Fig. 1 a; Bagchi et al, 2015;Inoue and Tsai, 2017); no peptides matching RTN3 or RTN4 were found in precipitated material derived from parental cells not expressing FLAG-tagged protein. To confirm that B12 and C18, as well as B14, associate with RTN3 or RTN4, anti-FLAG precipitations from parental cells and cells expressing 3xFLAG-B12, 3xFLAG-B14, or 3xFLAG-C18 were analyzed by SDS-PAGE and immunoblotting, with the precipitated material found to contain endogenous RTN4B ( Fig.…”

Section: Rtn4 Binds To the Er Membrane J Proteins B12 B14 And C18mentioning

confidence: 76%

Reticulon protects the integrity of the ER membrane during ER escape of large macromolecular protein complexes

Chen

Williams

Arvan

et al. 2020

Journal of Cell Biology

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Escape of large macromolecular complexes from the endoplasmic reticulum (ER), such as a viral particle or cellular aggregate, likely induces mechanical stress initiated on the luminal side of the ER membrane, which may threaten its integrity. How the ER responds to this threat remains unknown. Here we demonstrate that the cytosolic leaflet ER morphogenic protein reticulon (RTN) protects ER membrane integrity when polyomavirus SV40 escapes the ER to reach the cytosol en route to infection. SV40 coopts an intrinsic RTN function, as we also found that RTN prevents membrane damage during ER escape of a misfolded proinsulin aggregate destined for lysosomal degradation via ER-phagy. Our studies reveal that although ER membrane integrity may be threatened during ER escape of large macromolecular protein complexes, the action of RTN counters this, presumably by deploying its curvature-inducing activity to provide membrane flexibility and stability to limit mechanical stress imposed on the ER membrane.

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“…They oligomerize into a toroidal, ~2MDa complex, to which RNF170 is constitutively bound (7,13,14). By far the best defined function of erlins to date is to mediate IP3R processing (7), but other possible roles have been proposed, including binding cholesterol (16), regulation of lipid metabolism (16,17), and regulation of proteins that mediate SV40 exit from the ER (18). Interestingly, mutations to erlin1 and, more commonly, erlin2 have been linked to rare neurodegenerative diseases; e.g.…”

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confidence: 99%

The erlin2 T65I mutation inhibits erlin1/2 complex–mediated inositol 1,4,5-trisphosphate receptor ubiquitination and phosphatidylinositol 3-phosphate binding

Wright

Bonzerato

Sliter

et al. 2018

Journal of Biological Chemistry

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The erlin1/2 complex is a ~2MDa endoplasmic reticulum membrane-located ensemble of the ~40kDa type II membrane proteins erlin1 and erlin2. The best-defined function of this complex is to mediate the ubiquitination of activated inositol 1,4,5-trisphosphate receptors (IP3Rs) and their subsequent degradation. However, it remains unclear how mutations of the erlin1/2 complex affect its cellular function and cause cellular dysfunction and diseases such as hereditary spastic paraplegia. Here, we used gene editing to ablate erlin1 or erlin2 expression to better define their individual roles in the cell and examined the functional effects of a spastic paraplegia-linked mutation to erlin2 (threonine to isoleucine at position 65; T65I). Our results revealed that erlin2 is the dominant player in mediating the interaction between the erlin1/2 complex and IP3Rs, and that the T65I mutation dramatically inhibits this interaction and the ability of the erlin1/2 complex to promote IP3R ubiquitination and degradation. Remarkably, we also discovered that the erlin1/2 complex specifically binds to phosphatidylinositol 3-phosphate, that erlin2 binds this phospholipid much more strongly than does erlin1, that the binding is inhibited by T65I mutation of erlin2, and that multiple determinants within the erlin2 polypeptide comprise the phosphatidylinositol 3-phosphate-binding site.Overall, these results indicate that erlin2 is the primary mediator of the cellular roles of the erlin1/2 complex and that disease-linked mutations of erlin2 can affect both IP3R processing and lipid binding.

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Regulated Erlin-dependent release of the B12 transmembrane J-protein promotes ER membrane penetration of a non-enveloped virus

Cited by 21 publications

References 42 publications

Bag2 Is a Component of a Cytosolic Extraction Machinery That Promotes Membrane Penetration of a Nonenveloped Virus

Bag2 Is a Component of a Cytosolic Extraction Machinery That Promotes Membrane Penetration of a Nonenveloped Virus

Reticulon protects the integrity of the ER membrane during ER escape of large macromolecular protein complexes

The erlin2 T65I mutation inhibits erlin1/2 complex–mediated inositol 1,4,5-trisphosphate receptor ubiquitination and phosphatidylinositol 3-phosphate binding

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