A Novel Mammalian ER-located J-protein, DNAJB14, Can Accelerate ERAD of Misfolded Membrane Proteins

Sopha, Pattarawut; Kadokura, Hiroshi; Yamamoto, Yo; Takeuchi, Masato; Saito, Michiko; Tsuru, Akio; Kohno, Kenji

doi:10.1247/csf.12017

Cited by 31 publications

(26 citation statements)

References 22 publications

(51 reference statements)

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“…This interaction was specific to B14's cytosolic J domain as ERdj5, a lumenal J-protein, did not precipitate with any form of SGTA (Figure 2E). We performed the converse analysis by transfecting FLAG-tagged WT B14 or a mutant B14 defective in coupling to Hsc70 (H136Q) [37]. WT B14 but not H136Q B14 precipitated endogenous SGTA (Figure 2F).…”

Section: Resultsmentioning

confidence: 99%

A Cytosolic Chaperone Complexes with Dynamic Membrane J-Proteins and Mobilizes a Nonenveloped Virus out of the Endoplasmic Reticulum

et al. 2014

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Nonenveloped viruses undergo conformational changes that enable them to bind to, disrupt, and penetrate a biological membrane leading to successful infection. We assessed whether cytosolic factors play any role in the endoplasmic reticulum (ER) membrane penetration of the nonenveloped SV40. We find the cytosolic SGTA-Hsc70 complex interacts with the ER transmembrane J-proteins DnaJB14 (B14) and DnaJB12 (B12), two cellular factors previously implicated in SV40 infection. SGTA binds directly to SV40 and completes ER membrane penetration. During ER-to-cytosol transport of SV40, SGTA disengages from B14 and B12. Concomitant with this, SV40 triggers B14 and B12 to reorganize into discrete foci within the ER membrane. B14 must retain its ability to form foci and interact with SGTA-Hsc70 to promote SV40 infection. Our results identify a novel role for a cytosolic chaperone in the membrane penetration of a nonenveloped virus and raise the possibility that the SV40-induced foci represent cytosol entry sites.

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Section: Resultsmentioning

confidence: 99%

A Cytosolic Chaperone Complexes with Dynamic Membrane J-Proteins and Mobilizes a Nonenveloped Virus out of the Endoplasmic Reticulum

et al. 2014

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“…Notably, molecular chaperones Dnajb14 and Pfdn6 (prefoldin), both involved in protein folding and ERAD, were down-regulated in P23H and reversed by T1. Expression of Dnajb14 was reported to accelerate the degradation of misfolded membrane proteins such as the cystic fibrosis transmembrane conductance regulator Δ508 (CFTRΔ508) [64]. Prefoldins were previously reported to prevent ubiquitinated-protein aggregation under ER-stress [65-67].…”

Section: Resultsmentioning

confidence: 99%

Transcriptome profiling of NIH3T3 cell lines expressing opsin and the P23H opsin mutant identifies candidate drugs for the treatment of retinitis pigmentosa

Chen

Brooks

Gieser

et al. 2017

Pharmacological Research

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Mammalian cells are commonly employed in screening assays to identify active compounds that could potentially affect the progression of different human diseases including retinitis pigmentosa (RP), a class of inherited diseases causing retinal degeneration with compromised vision. Using transcriptome analysis, we compared NIH3T3 cells expressing wildtype (WT) rod opsin with a retinal disease-causing single P23H mutation. Surprisingly, heterologous expression of WT opsin in NIH3T3 cells caused more than a 2-fold change in 783 out of 16,888 protein coding transcripts. The perturbed genes encoded extracellular matrix proteins, growth factors, cytoskeleton proteins, glycoproteins and metalloproteases involved in cell adhesion, morphology and migration. A different set of 347 transcripts was either up- or down-regulated when the P23H mutant opsin was expressed suggesting an altered molecular perturbation compared to WT opsin. Transcriptome perturbations elicited by drug candidates aimed at mitigating the effects of the mutant protein revealed that different drugs targeted distinct molecular pathways that resulted in a similar phenotype selected by a cell-based high-throughput screen. Thus, transcriptome profiling can provide essential information about the therapeutic potential of a candidate drug to restore normal gene expression in pathological conditions.

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“…Several host components required by PyVs for infection are implicated in ERAD, including BAP31, B12, and B14 (23)(24)(25)(26)(27)(28)(29)(30)34). However, the precise functions of these proteins in ERAD are not clear, and whether C18 participates in ERAD is completely unknown.…”

Section: Discussionmentioning

confidence: 99%

“…ERAD is a quality control process that functions to eliminate misfolded proteins from the ER by retrotranslocating them into cytosol for proteasomal degradation (24). SV40 and other PyVs utilize selective ERAD components, as well as the ER membrane-bound J proteins DnaJB12 (B12), DnaJB14 (B14), and DnaJC18 (C18), to reach the cytosol and cause infection (23)(24)(25)(26)(27)(28)(29)(30). The individual contribution of each membrane-bound J protein, their potential redundancy, and how they may cooperate to promote successful PyV membrane penetration and infection are largely unknown.…”

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confidence: 99%

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The Endoplasmic Reticulum Membrane J Protein C18 Executes a Distinct Role in Promoting Simian Virus 40 Membrane Penetration

Bagchi

Walczak

Tsai

2015

J Virol

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The nonenveloped simian virus 40 (SV40) hijacks the three endoplasmic reticulum (ER) membrane-bound J proteins B12, B14, and C18 to escape from the ER into the cytosol en route to successful infection. How C18 controls SV40 ER-to-cytosol membrane penetration is the least understood of these processes. We previously found that SV40 triggers B12 and B14 to reorganize into discrete puncta in the ER membrane called foci, structures postulated to represent the cytosol entry site (C. P. Walczak, M. S. Ravindran, T. Inoue, and B. Tsai, PLoS Pathog 10:e1004007, 2014). We now find that SV40 also recruits C18 to the virus-induced B12/B14 foci. Importantly, the C18 foci harbor membrane penetration-competent SV40, further implicating this structure as the membrane penetration site. Consistent with this, a mutant SV40 that cannot penetrate the ER membrane and promote infection fails to induce C18 foci. C18 also regulates the recruitment of B12/B14 into the foci. In contrast to B14, C18's cytosolic Hsc70-binding J domain, but not the lumenal domain, is essential for its targeting to the foci; this J domain likewise is necessary to support SV40 infection. Knockdown-rescue experiments reveal that C18 executes a role that is not redundant with those of B12/B14 during SV40 infection. Collectively, our data illuminate C18's contribution to SV40 ER membrane penetration, strengthening the idea that SV40-triggered foci are critical for cytosol entry. IMPORTANCEPolyomaviruses (PyVs) cause devastating human diseases, particularly in immunocompromised patients. As this virus family continues to be a significant human pathogen, clarifying the molecular basis of their cellular entry pathway remains a high priority. To infect cells, PyV traffics from the cell surface to the ER, where it penetrates the ER membrane to reach the cytosol. In the cytosol, the virus moves to the nucleus to cause infection. ER-to-cytosol membrane penetration is a critical yet mysterious infection step. In this study, we clarify the role of an ER membrane protein called C18 in mobilizing the simian PyV SV40, a PyV archetype, from the ER into the cytosol. Our findings also support the hypothesis that SV40 induces the formation of punctate structures in the ER membrane, called foci, that serve as the portal for cytosol entry of the virus. While polyomaviruses (PyVs) are known to establish asymptomatic persistent infections in the kidney, blood, skin, and brain of healthy individuals, they carry the potential to cause debilitating diseases, especially during immunosuppression. For example, infections caused by the human BK, JC, and Merkel cell PyVs can lead to PyV-associated nephropathy, progressive multifocal leukoencephalopathy, and Merkel cell carcinoma, respectively (1, 2). Simian virus 40 (SV40) traditionally has been used as a model for studying this virus family and has structural and genetic similarities to human PyVs. SV40 and all other PyVs are nonenveloped icosahedral particles, approximately 45 nm in diameter, and contain a double-stranded DNA gen...

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A Novel Mammalian ER-located J-protein, DNAJB14, Can Accelerate ERAD of Misfolded Membrane Proteins

Cited by 31 publications

References 22 publications

A Cytosolic Chaperone Complexes with Dynamic Membrane J-Proteins and Mobilizes a Nonenveloped Virus out of the Endoplasmic Reticulum

A Cytosolic Chaperone Complexes with Dynamic Membrane J-Proteins and Mobilizes a Nonenveloped Virus out of the Endoplasmic Reticulum

Transcriptome profiling of NIH3T3 cell lines expressing opsin and the P23H opsin mutant identifies candidate drugs for the treatment of retinitis pigmentosa

The Endoplasmic Reticulum Membrane J Protein C18 Executes a Distinct Role in Promoting Simian Virus 40 Membrane Penetration

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