Polyubiquitination Is Required for US11-dependent Movement of MHC Class I Heavy Chain from Endoplasmic Reticulum into Cytosol

Shamu, Caroline E.; Flierman, Dennis; Ploegh, Hidde L.; Rapoport, Tom A.; Chau, Vincent

doi:10.1091/mbc.12.8.2546

Cited by 119 publications

(119 citation statements)

References 28 publications

Supporting

Mentioning

113

Contrasting

Order By: Relevance

“…S8D), although it did block cross-presentation (20). This differential effect is relevant to a previously proposed mechanism whereby ubiquitin conjugation serves as a "ratchet" to dislocate ERmisfolded proteins into the cytosol, a model based on the fact that most of the proteins exported from the ER are polyubiquitinylated (31,32). However, our results indicate that ubiquitination is essential for the proteasome-mediated processing of T-cell epitopes but is dispensable for the translocation of endosomal antigen into the cytosol.…”

Section: Discussionsupporting

confidence: 51%

Heat shock protein 90 (HSP90) contributes to cytosolic translocation of extracellular antigen for cross-presentation by dendritic cells

Imai¹,

Kato²,

Kajiwara³

et al. 2011

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

130

123

View full text Add to dashboard Cite

In antigen (Ag) cross-presentation, dendritic cells (DCs) take up extracellular Ag and translocate them from the endosome to the cytosol for proteasomal degradation. The processed peptides can enter the conventional MHC I pathway. The molecules responsible for the translocation of Ag across the endosomal membrane into the cytosol are unknown. Here we demonstrate that heat shock protein 90 (HSP90) is critical for this step. Cross-presentation and -priming were decreased in both HSP90α-null DCs and mice. CD8α + DC apoptosis mediated by translocation of exogenous cytochrome c to the cytosol was also eliminated in HSP90α-null mice. Ag translocation into the cytosol was diminished in HSP90α-null DCs and in DCs treated with an HSP90 inhibitor. Internalized Ag was associated with HSP90 and translocated to the cytosol, a process abrogated by the HSP90 inhibitor. Ag within purified phagosomes was released in an HSP90-dependent manner. These results demonstrate the important role of HSP90 in cross-presentation by pulling endosomal Ag out into the cytosol.

show abstract

Section: Discussionsupporting

confidence: 51%

Heat shock protein 90 (HSP90) contributes to cytosolic translocation of extracellular antigen for cross-presentation by dendritic cells

Imai¹,

Kato²,

Kajiwara³

et al. 2011

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

130

123

View full text Add to dashboard Cite

show abstract

“…It has been previously proposed that for some ERAD substrates dislocation involves a step in which luminal domains are only partially exposed to the cytosolic side (32,33). To investigate this point, we used two additional constructs in which the BAP tag was moved to positions on the luminal side proximal to the transmembrane domains of both CD4 and Tetherin (18 and 12 amino acids, respectively) (Fig.…”

Section: Resultsmentioning

confidence: 99%

CD4 and BST-2/Tetherin Proteins Retro-translocate from Endoplasmic Reticulum to Cytosol as Partially Folded and Multimeric Molecules

Petris

Casini

Sasset

et al. 2014

Journal of Biological Chemistry

View full text Add to dashboard Cite

Background: CD4 and Tetherin are stabilized through intrachain and interchain disulfide bonds, respectively. Results: CD4 and Tetherin retro-translocate from ER to cytosol with oxidized disulfide bridges as folded and multimeric molecules. Conclusion: Cysteines reduction is not a prerequisite for ER to cytosol dislocation. Significance: Our observations challenge the requirements of reduction and unfolding before dislocation.

show abstract

“…Retrotranslocation is facilitated by the cytosolic Cdc48p-Ufd1p-Npl4p complex, which associates with Hrd1p and Doa10p via membrane-bound Ubx2p (4, 8 -10), and likely uses ATP hydrolysis to both unfold ERAD substrates and extract them from the ER membrane (11)(12)(13). Polyubiquitination then occurs either simultaneously with or immediately after retrotranslocation (14,15).…”

Section: The Endoplasmic Reticulum (Er)mentioning

confidence: 99%

SPFH2 Mediates the Endoplasmic Reticulum-associated Degradation of Inositol 1,4,5-Trisphosphate Receptors and Other Substrates in Mammalian Cells

Pearce

Wang

Kelley

et al. 2007

Journal of Biological Chemistry

101

163

View full text Add to dashboard Cite

Inositol 1,4,5-trisphosphate (IP 3 ) receptors are endoplasmic reticulum (ER) membrane calcium channels that, upon activation, become substrates for the ER-associated degradation (ERAD) pathway. Although it is clear that IP 3 receptors are polyubiquitinated upon activation and are transferred to the proteasome by a p97-based complex, currently nothing is known about the proteins that initially select activated IP 3 receptors for ERAD. Here, we sought to identify novel proteins that associate with and mediate the ERAD of endogenous activated IP 3 receptors. SPFH2, an uncharacterized SPFH domaincontaining protein, rapidly associated with IP 3 receptors in a manner that preceded significant polyubiquitination and the association of p97 and related proteins. SPFH2 was found to be an ER membrane protein largely residing within the ER lumen and in resting and stimulated cells was linked to ERAD pathway components, apparently via endogenous substrates undergoing degradation. Suppression of SPFH2 expression by RNA interference markedly inhibited IP 3 receptor polyubiquitination and degradation and the processing of other ERAD substrates. Overall, these studies identify SPFH2 as a key ERAD pathway component and suggest that it may act as a substrate recognition factor. The endoplasmic reticulum (ER)2 -associated degradation (ERAD) pathway is responsible for the degradation of aberrant proteins in the ER (1) and, in addition to this "quality control" function, also accounts for the degradation of several metabolically regulated, native ER proteins (2, 3). The essential features of the ERAD pathway are substrate recognition, polyubiquitination, and delivery to the 26 S proteasome, which is located in the cytosol (1). Much of our understanding of the ERAD pathway has been obtained using yeast as a model system, and although there are many parallels between the yeast and mammalian ERAD pathways, there appear to be some key differences. Most notably, mammalian cells have additional components that add diversity and complexity to substrate recognition and processing (4).Quite a lot is known about how ERAD substrates are polyubiquitinated and transferred to the proteasome. Studies in yeast suggest that ER luminal substrates and membrane substrates with aberrant luminal or membrane domains are polyubiquitinated by an ER membrane protein complex containing the ubiquitin ligase (E3) Hrd1p, whereas membrane substrates with aberrant cytosolic domains are targeted by a complex containing the E3 Doa10p (4). Hrd3p binds to and regulates Hrd1p (5), and together with the ER luminal lectin Yos9p, may use its large luminal domain to recruit ERAD substrates to a putative "retrotranslocation" channel in the ER membrane (6 -8). Retrotranslocation is facilitated by the cytosolic Cdc48p-Ufd1p-Npl4p complex, which associates with Hrd1p and Doa10p via membrane-bound Ubx2p (4, 8 -10), and likely uses ATP hydrolysis to both unfold ERAD substrates and extract them from the ER membrane (11-13). Polyubiquitination then occurs either simultaneously wit...

show abstract

Polyubiquitination Is Required for US11-dependent Movement of MHC Class I Heavy Chain from Endoplasmic Reticulum into Cytosol

Cited by 119 publications

References 28 publications

Heat shock protein 90 (HSP90) contributes to cytosolic translocation of extracellular antigen for cross-presentation by dendritic cells

Heat shock protein 90 (HSP90) contributes to cytosolic translocation of extracellular antigen for cross-presentation by dendritic cells

CD4 and BST-2/Tetherin Proteins Retro-translocate from Endoplasmic Reticulum to Cytosol as Partially Folded and Multimeric Molecules

SPFH2 Mediates the Endoplasmic Reticulum-associated Degradation of Inositol 1,4,5-Trisphosphate Receptors and Other Substrates in Mammalian Cells

Contact Info

Product

Resources

About