Promotion of Endoplasmic Reticulum-Associated Degradation of Procathepsin D by Human Herpesvirus 8-Encoded Viral Interleukin-6

Chen, Daming; Nicholas, John

doi:10.1128/jvi.00375-15

Cited by 11 publications

(17 citation statements)

References 37 publications

(60 reference statements)

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“…In contrast, vIL-6, VKORC1v2, and pCatD can cocomplex and, indeed, vIL-6 promotes the interaction of pCatD with VKORC1v2 (7). We hypothesize that competition versus cocomplexing may, in part at least, determine the fate of VKORC1v2-interacting proteins in relation to their regulation by vIL-6 via the receptor, competition enabling removal of VKORC1v2-interacting IGF2R from the prodegradation activities of VKORC1v2 through ERAD protein interactions (4). We have provided evidence here that VKORC1v2-IGF2R interaction, mediated via VKORC1v2 "vBD" residues 31 to 39, is necessary for VKORC1v2 suppression of IGF2R.…”

Section: Influence Of Igf2r On Pel Cell Viability and Hhv-8 Productivmentioning

confidence: 94%

“…Activities of vIL-6 are mediated via interactions with the gp130 (IL-6) signaling receptor and also the ER membrane protein vitamin K epoxide reductase complex subunit 1 variant-2 (VKORC1v2) (1)(2)(3). The former interaction promotes gp130-mediated mitogen-activated protein kinase and signal transducer and activator of transcription (STAT) signaling; the latter interaction affects protein folding through associations with calnexin cycle enzymes and also regulates ER-associated degradation (ERAD) via interactions with ERAD chaperone and translocon proteins (4,5). Although vIL-6 is produced in abundance during productive (lytic) replication, it is also expressed at low, functional levels during latency in primary effusion lymphoma (PEL) B cells and is important for maintenance of cell viability in examined PEL cell lines (6).…”

mentioning

confidence: 99%

“…These axes of vIL-6 function are involved also in the vIL-6-mediated promotion of HHV-8 productive replication in reactivated PEL and/or endothelial cells, with demonstrable positive contributions of gp130-activated STAT3 signaling, specifically, to virus replication (3,7). Proviability and proreplication activities of vIL-6 via VKORC1v2 in PEL cells involve the suppression of proapoptotic cathepsin D (CatD) expression, via vIL-6/VKORC1v2-enhanced ERAD of ER-transiting pro-CatD (4,7). Pro-folding activities of vIL-6 via VKORC1v2 and calnexin cycle protein interactions (5) could conceivably also contribute to virus latent and/or lytic biology.…”

mentioning

confidence: 99%

“…Regulation of IGF2R expression by VKORC1v2 and vIL-6. We previously identified lysosomal protein cathepsin D (CatD) as being regulated (negatively) by vIL-6 via its association with VKORC1v2; suppression of CatD was found to involve interactions of VKORC1v2, vIL-6 and full-length, unprocessed pro-cathepsin D (pCatD) with the ER-associated degradation (ERAD) machinery (4). In view of this, we hypothesized that the interaction of VKORC1v2 with IGF2R might affect IGF2R expression.…”

mentioning

confidence: 99%

“…(C) Chitin bead-based precipitation analyses of (endogenous) IGF2R interactions with VKORC1v2-CBD (v2-CBD) and vIL-6-CBD; VKORC1v1-CBD (v1-CBD) and empty vector were transfected into parallel cultures to provide negative controls. ment (1,6), we reasoned that these proteins were likely to act on nascent, ER-transiting IGF2R to mediate its regulation, for example through effects on protein folding and/or ERAD, known to be affected by vIL-6 and VKORC1v2 (4,5). To test this, we generated a plasmid vector expressing IGF2R protein fused to HaloTag (21), allowing fluorescence pulse-labeling of the protein in transfected cells.…”

mentioning

confidence: 99%

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Insulin-Like Growth Factor 2 Receptor Expression Is Promoted by Human Herpesvirus 8-Encoded Interleukin-6 and Contributes to Viral Latency and Productive Replication

Chen

Xiang

et al. 2019

J Virol

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Human herpesvirus 8 (HHV-8) viral interleukin-6 (vIL-6) localizes largely to the endoplasmic reticulum (ER) and here associates functionally with both the gp130 signal transducer and the novel ER membrane protein vitamin K epoxide reductase complex subunit 1 variant-2 (VKORC1v2). The latter interaction contributes to the viability of latently infected primary effusion lymphoma (PEL) cells and to HHV-8 productive replication, in part via promotion of ER-associated degradation (ERAD) of nascent procathepsin D (pCatD) and consequent suppression of lysosome-localized proapoptotic mature CatD. Here we report that VKORC1v2 associates with insulin-like growth factor 2 receptor (IGF2R), also known as cation-independent mannose-6-phosphate receptor, which is involved in trafficking of mannose-6-phosphate-conjugated glycoproteins to lysosomes. VKORC1v2 effected reduced IGF2R expression in a manner dependent on VKORC1v2-IGF2R interaction, while vIL-6, which could inhibit VKORC1v2-IGF2R interaction, effected increased expression of IGF2R. These effects were independent of changes in IGF2R mRNA levels, indicating likely posttranslational mechanisms. In kinetic analyses involving labeling of either newly synthesized or preexisting IGF2R, vIL-6 promoted accumulation of the former while having no detectable effect on the latter. Furthermore, vIL-6 led to decreased K48-linked ubiquitination of IGF2R and suppression of ERAD proteins effected increased IGF2R expression and loss of IGF2R regulation by vIL-6. Depletion-based experiments identified IGF2R as a promoter of PEL cell viability and virus yields from lytically reactivated cultures. Our findings identify ER-transiting nascent IGF2R as an interaction partner of VKORC1v2 and target of vIL-6 regulation and IGF2R as a positive contributor to HHV-8 biology, thereby extending understanding of the mechanisms of VKORC1v2-associated vIL-6 function. IMPORTANCE HHV-8 vIL-6 promotes productive replication in the context of reactivated lytic replication in primary effusion lymphoma (PEL) and endothelial cells and sustains latently infected PEL cell viability. Viral IL-6 is also considered to contribute significantly to HHV-8-associated pathogenesis, since vIL-6 can promote cell proliferation, cell survival, and angiogenesis that are characteristic of HHV-8-associated Kaposi's sarcoma, PEL and multicentric Castleman's disease (MCD), in addition to proinflammatory activities observed in MCD-like "Kaposi's sarcoma-associated herpesvirus-induced cytokine syndrome." We show in the present study that vIL-6 can promote productive replication and latent PEL cell viability through upregulation of the mannose-6-phosphate-and peptide hormone-interacting receptor IGF2R, which is a positive factor in HHV-8 biology via these activities. VKORC1v2-enhanced ER-associated degradation of IGF2R and vIL-6 promotion of IGF2R expression through prevention of its interaction with VKORC1v2 and consequent rescue from degradation represent newly recognized activities of VKOCR1v2 and vIL-6. KEYWORDS ER-associated d...

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Section: Influence Of Igf2r On Pel Cell Viability and Hhv-8 Productivmentioning

confidence: 94%