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

Li, Qian; Chen, Daming; Xiang, Qiwang; Nicholas, John

doi:10.1128/jvi.02026-18

Cited by 8 publications

(11 citation statements)

References 35 publications

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“…Among these was the multifunctional receptor IGF2R, a protein involved in intracellular retrograde transport 87 . IGF2R was reported to support the replication of the gamma herpesvirus HHV-8 and the retrovirus HIV-1 88,89 , and our results also establish it as a pro-viral factor during HCMV infection. While the disruption and reduction of IGF2R signal around the nucleus early in infection is consistent with the Golgi reorganization by HCMV 12 , the IGF2R localization to the assembly complex late in infection and the inhibitory effect of its knockout on virus production suggest that HCMV hijacks IGF2R to coordinate cell signaling.…”

Section: Prm Validation Igf2rsupporting

confidence: 79%

Temporal dynamics of protein complex formation and dissociation during human cytomegalovirus infection

et al. 2020

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The co-evolution and co-existence of viral pathogens with their hosts for millions of years is reflected in dynamic virus-host protein-protein interactions (PPIs) that are intrinsic to the spread of infections. Here, we investigate the system-wide dynamics of protein complexes throughout infection with the herpesvirus, human cytomegalovirus (HCMV). Integrating thermal shift assays and mass spectrometry quantification with virology and microscopy, we monitor the temporal formation and dissociation of hundreds of functional protein complexes and the dynamics of host-host, virus-host, and virus-virus PPIs. We establish pro-viral roles for cellular protein complexes and translocating proteins. We show the HCMV receptor integrin beta 1 dissociates from extracellular matrix proteins, becoming internalized with CD63, which is necessary for virus production. Moreover, this approach facilitates characterization of essential viral proteins, such as pUL52. This study of temporal protein complex dynamics provides insights into mechanisms of HCMV infection and a resource for biological and therapeutic studies.

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Section: Prm Validation Igf2rsupporting

confidence: 79%

Temporal dynamics of protein complex formation and dissociation during human cytomegalovirus infection

et al. 2020

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“…Previous studies of vIL-6 interactions and activities had identified the direct physical interaction of vIL-6 with VKORC1v2 and gp130, the occurrence of these interactions in the ER compartment, and their contributions to latently infected PEL cell viability and to HHV-8 productive replication in PEL and/or endothelial cell lines (11,(16)(17)(18)24). In the context of PEL cells, vIL-6, VKORC1v2, and vIL-6-VKORC1v2 interactions were associated with regulation of the levels of endogenously expressed CatD (proapoptotic) and IGF2R (proviability/replication) via VKORC1v2-associated promotion of and rescue from ERAD, respectively (19,20). The observed enhanced expression of IGF2R may be effected via VKORC1v2 interaction with calnexin cycle proteins UGGT1 and GlucII to promote protein folding and escape of nascent IGF2R from ERAD and the ER as correctly folded protein (14,36).…”

Section: Discussionmentioning

confidence: 98%

“…5E). In the context of PEL cells, VKORC1v2 was found to associate with pro-CatD and IGF2R, which were regulated negatively and positively, respectively, by vIL-6; these proteins were associated with suppression (CatD) and promotion (IGF2R) of PEL cell viability and productive replication in these cells (20,24). To investigate potential biological activity of VKORC1v2 in iSLK cells, we generated VKORC1v2knockout and control (Cas9 ϩ /gRNA Ϫ ) cell lines (see Materials and Methods).…”

Section: Bindingmentioning

confidence: 94%

“…With respect to VKORC1v2-associated activities, it is notable that both VKORC1v2 and vIL-6 coassociate with UGGT1 and GlucII␣ and that vIL-6 promotes protein folding, in the contexts of both transfected cells (in a VKORC1v2dependent manner) and infected cells (14), although the mechanistic basis of this activity has not been established. Also of relevance is that interaction of vIL-6 with VKORC1v2 promotes ER-associated degradation (ERAD) of the ER-transiting precursor of the stress-released proapoptotic protein cathepsin D (CatD) and, conversely, inhibits ERAD of nascent insulin-like growth factor 2 receptor/cation-independent mannose-6phosphate receptor (IGF2R/CI-MPR) to promote expression of this proviability factor (19,20). Thus, there are various activities that appear to be regulated by vIL-6 via interaction with VKORC1v2.…”

mentioning

confidence: 99%

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Genetic Analyses of Contributions of Viral Interleukin-6 Interactions and Signaling to Human Herpesvirus 8 Productive Replication

Xiang

Chen

et al. 2020

J Virol

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Human herpesvirus 8 (HHV-8) viral interleukin-6 (vIL-6) is a cytokine that is poorly secreted and largely localized to the endoplasmic reticulum (ER). It has been implicated, along with other HHV-8 pro-inflammatory and/or angiogenic viral proteins, in HHV-8-associated Kaposi's sarcoma, primary effusion lymphoma (PEL), and multicentric Castleman's disease (MCD), in addition to an MCD-related disorder involving systemic elevation of pro-inflammatory cytokines, including vIL-6 and human IL-6 (hIL-6). In these diseases, lytic (productive) replication, in addition to viral latency, is believed to play a critical role. Pro-replication activity of vIL-6 has been identified experimentally in PEL and endothelial cells, but the relative contributions of different vIL-6 interactions have not been established. Productive interactions of vIL-6 with the IL-6 signal transducer, gp130, can occur within the ER, but vIL-6 also interacts in the ER with a non-signaling receptor called vitamin K epoxide reductase complex subunit 1 variant-2 (VKORC1v2), calnexin, and VKORC1v2- and calnexin-associated proteins UDP-glucose:glycoprotein glucosyltransferase 1 (UGGT1) and glucosidase II (GlucII). Here, we report the systematic characterization of interaction-altered vIL-6 variants and the lytic phenotypes of recombinant viruses expressing selected variants. Our data identify the critical importance of vIL-6 and its ER-localized activity via gp130 to productive replication in iSLK (inducible epithelial) cells, absence of detectable involvement of vIL-6 interactions with VKORC1v2, GlucII or UGGT1, and the insufficiency and lack of direct contributory effects of extracellular signaling by vIL-6 or hIL-6. These findings, obtained through genetics-based approaches, complement and extend previous analyses of vIL-6 activity. IMPORTANCE Human herpesvirus 8 (HHV-8)-encoded viral interleukin-6 (vIL-6) was the first viral IL-6 homologue to be identified. Experimental and clinical evidence suggests that vIL-6 is important for the onset and/or progression of HHV-8-associated endothelial- and B-cell pathologies, including AIDS-associated Kaposi's sarcoma and multicentric Castleman's disease. The protein is unusual in its poor secretion from cells and its intracellular activity; it interacts, directly or indirectly, with a number of proteins beyond the IL-6 signal transducer, gp130, and can mediate activities through these interactions in the endoplasmic reticulum. Here, we characterize with respect to protein interactions and signal transducing activity a panel of vIL-6 variants and utilize HHV-8 mutant viruses expressing selected variants in phenotypic analyses. Our findings establish the importance of vIL-6 in HHV-8 productive replication and the contributions of individual vIL-6-protein interactions to HHV-8 lytic biology. This work furthers understanding of the biological significance of vIL-6 and its unique intracellular interactions.

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“…Upon infection B-lymphocytes induce several impairments of the immune system due to vIL-6 production and the induction of chronic inflammation [51,66,72]. Recently Li et al [73] found that vIL-6, mainly localized in the endoplasmic reticulum, has a pivotal role in viral metabolism, viral lytic replication and enhancement of cell growth. It also contributes to HHV8 infectivity and pathogenesis by the stimulation of cell multiplication and induction of neo-angiogenesis.…”

Section: Hhv8 and Cyclooxygenase: Induction And Suppression Of Immunementioning

confidence: 99%

Human Herpesvirus 8 and Host-Cell Interaction: Long-Lasting Physiological Modifications, Inflammation and Related Chronic Diseases

2020

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Oncogenic and latent-persistent viruses belonging to both DNA and RNA groups are known to cause serious metabolism alterations. Among these, the Human Herpesvirus 8 (HHV8) infection induces stable modifications in biochemistry and cellular metabolism, which in turn affect its own pathological properties. HHV8 enhances the expression of insulin receptors, supports the accumulation of neutral lipids in cytoplasmic lipid droplets and induces alterations in both triglycerides and cholesterol metabolism in endothelial cells. In addition, HHV8 is also known to modify immune response and cytokine production with implications for cell oxidative status (i.e., reactive oxygen species activation). This review underlines the recent findings regarding the role of latent and persistent HHV8 viral infection in host physiology and pathogenesis.

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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

Cited by 8 publications

References 35 publications

Temporal dynamics of protein complex formation and dissociation during human cytomegalovirus infection

Temporal dynamics of protein complex formation and dissociation during human cytomegalovirus infection

Genetic Analyses of Contributions of Viral Interleukin-6 Interactions and Signaling to Human Herpesvirus 8 Productive Replication

Human Herpesvirus 8 and Host-Cell Interaction: Long-Lasting Physiological Modifications, Inflammation and Related Chronic Diseases

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