Protein Unfolding Is Not a Prerequisite for Endoplasmic Reticulum-to-Cytosol Dislocation

Tirosh, Boaz; Furman, Margo H.; Tortorella, Domenico; Ploegh, Hidde L.

doi:10.1074/jbc.m210158200

Cited by 91 publications

(54 citation statements)

References 35 publications

(42 reference statements)

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“…3c) was longer than that of endogenous heavy chain, which has been reported to bẽ 3-5 min (Wiertz et al, 1996b). The observation that the chimeric class I molecules were degraded with slower kinetics than endogenous heavy chains (Fiebiger et al, 2002;Story et al, 1999;Tirosh et al, 2003). Nevertheless, these results imply that chimeric HC-CTAP molecules were targeted for the proteasomal degradation in US2-expressing cells.…”

Section: Hc-ctap Is Degraded In a Gpus2-dependent Mannercontrasting

confidence: 47%

Endoplasmic reticulum chaperones participate in human cytomegalovirus US2-mediated degradation of class I major histocompatibility complex molecules

Orešić

Tortorella

2008

Journal of General Virology

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Inhibition of cell-surface expression of major histocompatibility complex class I molecules by human cytomegalovirus (HCMV, a b-herpesvirus) promotes escape from recognition by CD8 + cytotoxic T cells. The HCMV US2 and US11 gene products induce class I downregulation during the early phase of HCMV infection by facilitating the degradation of class I heavy chains. The HCMV proteins promote the transport of the class I heavy chains across the endoplasmic reticulum (ER) membrane into the cytosol by a process referred to as 'dislocation', which is then followed by proteasome degradation. This process has striking similarities to the degradation of misfolded ER proteins mediated by ER quality control. Even though the major steps of the dislocation reaction have been characterized, the cellular proteins, specifically the ER chaperones involved in targeting class I for dislocation, have not been fully delineated. To elucidate the chaperones involved in HCMV-mediated class I dislocation, we utilized a chimeric class I heavy chain with an affinity tag at its carboxy terminus. Interestingly, US2 but not US11 continued to target the class I chimera for destruction, suggesting a structural limitation for US11-mediated degradation. Association studies in US2 cells and in cells that express a US2 mutant, US2-186HA, revealed that class I specifically interacts with calnexin, BiP and calreticulin. These findings demonstrate that US2-mediated class I destruction utilizes specific chaperones to facilitate class I dislocation. The data suggest a more general model in which the chaperones that mediate protein folding may also function during ER quality control to eliminate aberrant ER proteins.

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Section: Hc-ctap Is Degraded In a Gpus2-dependent Mannercontrasting

confidence: 47%

Endoplasmic reticulum chaperones participate in human cytomegalovirus US2-mediated degradation of class I major histocompatibility complex molecules

Orešić

Tortorella

2008

Journal of General Virology

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“…There are few examples reported in literature of artificial substrates that seem to be dislocated as folded molecules (50,51). These evidences seem to suggest, in a very indirect way, that unfolding is not a prerequisite for crossing the ER lipid bilayer.…”

Section: Discussionmentioning

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

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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.

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“…U373-MG astrocytoma cells transfected with US11 have been described previously (23). All astrocytoma cell lines were cultured in Dulbecco's modified Eagle's medium (DMEM) as described previously (27). Tet-On systems (Clontech, Palo Alto, Calif.) for US2 and US11 in the U373 cell lines were constructed according to the manufacturer's guidelines.…”

Section: Methodsmentioning

confidence: 99%

Human Cytomegalovirus Protein US11 Provokes an Unfolded Protein Response That May Facilitate the Degradation of Class I Major Histocompatibility Complex Products

Tirosh

Iwakoshi

Lilley

et al. 2005

J Virol

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The human cytomegalovirus (HCMV) glycoprotein US11 diverts class I major histocompatibility complex (MHC) heavy chains (HC) from the endoplasmic reticulum (ER) to the cytosol, where HC are subjected to proteasome-mediated degradation. In mouse embryonic fibroblasts that are deficient for X-box binding protein 1 (XBP-1), a key transcription factor in the unfolded protein response (UPR) pathway, we show that degradation of endogenous mouse HC is impaired. Moreover, the rate of US11-mediated degradation of ectopically expressed HLA-A2 is reduced when XBP-1 is absent. In the human astrocytoma cell line U373, turning on expression of US11, but not US2, is sufficient to induce a UPR, as manifested by upregulation of the ER chaperone Bip and by splicing of XBP-1 mRNA. In the presence of dominant-negative versions of XBP-1 and activating transcription factor 6, the kinetics of class I MHC HC degradation were delayed when expression of US11 was turned on. The magnitude of these effects, while reproducible, was modest. Conversely, in cells that stably express high levels of US11, the degradation of HC is not affected by the presence of the dominant negative effectors of the UPR. An infection of human foreskin fibroblasts with human cytomegalovirus induced XBP-1 splicing in a manner that coincides with US11 expression. We conclude that the contribution of the UPR is more pronounced on HC degradation shortly after induction of US11 expression and that US11 is sufficient to induce such a response.The human cytomegalovirus (HCMV) glycoproteins US2 and US11 specifically target class I major histocompatibility complex (MHC) heavy chains (HC) for dislocation from the endoplasmic reticulum (ER) membrane to the cytosol, where they are degraded by the proteasome. Many similarities exist between the series of events catalyzed by these viral glycoproteins and disposal of misfolded proteins in the ER. Although the exact mechanism by which class I HC are rerouted for dislocation by US2 and US11 is still unknown, studies using mutants of US2, US11, and class I HC show that dislocation by US11 and US2 involves distinct mechanisms. One of these distinctions is the unique role of the US11 transmembrane (TM) domain, which mediates the interaction with the transmembrane protein Derlin-1 (15). This interaction is necessary for class I MHC dislocation, since a single amino acid replacement, Q192L in the TM of US11 (Q192L) abolishes this interaction and, with it, the ability to dislocate class I HC (15, 16).

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Protein Unfolding Is Not a Prerequisite for Endoplasmic Reticulum-to-Cytosol Dislocation

Cited by 91 publications

References 35 publications

Endoplasmic reticulum chaperones participate in human cytomegalovirus US2-mediated degradation of class I major histocompatibility complex molecules

Endoplasmic reticulum chaperones participate in human cytomegalovirus US2-mediated degradation of class I major histocompatibility complex molecules

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

Human Cytomegalovirus Protein US11 Provokes an Unfolded Protein Response That May Facilitate the Degradation of Class I Major Histocompatibility Complex Products

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