Kaposi’s Sarcoma-Associated Herpesvirus Lytic Replication Interferes with mTORC1 Regulation of Autophagy and Viral Protein Synthesis

Abstract

All viruses require host cell machinery to synthesize viral proteins. A host cell protein complex known as mechanistic target of rapamycin complex 1 (mTORC1) is a master regulator of protein synthesis. Under nutrient-rich conditions, mTORC1 is active and promotes protein synthesis to meet cellular anabolic demands. Under nutrient-poor conditions or under stress, mTORC1 is rapidly inhibited, global protein synthesis is arrested, and a cellular catabolic process known as autophagy is activated. Kaposi’s sarcoma-associated herpesvirus (KSHV) stimulates mTORC1 activity and utilizes host machinery to synthesize viral proteins. However, we discovered that mTORC1 activity was largely dispensable for viral protein synthesis, genome replication, and the release of infectious progeny. Likewise, during lytic replication, mTORC1 was no longer able to control autophagy. These findings suggest that KSHV undermines mTORC1-dependent cellular processes during the lytic cycle to ensure efficient viral replication.

Kaposi’s sarcoma-associated herpesvirus (KSHV) utilizes the NDP52/CALCOCO2 selective autophagy receptor to disassemble processing bodies

“…However, once cancer is established, autophagic flux promotes progression of established tumours by a variety of approaches, including promoting a pro-tumourigenic and proinflammatory environment (Vescovo et al, 2020;Liu & Debnath, 2016). Consistent with this, markers of upregulated autophagic flux are elevated in several cancers and in primary effusion lymphoma cells that harbour the KSHV genome as a latent episome (Pringle et al, 2019;reviewed in Wu et al, 2012), suggesting that at this latent stage, viral gene products enhance autophagy to maintain tumourigenesis. This sensible model is, in reality, an oversimplification, as we know that KSHV gene products both enhance and block autophagic flux during both latent and lytic KSHV phases (Vescovo et al, 2020;Cirone, 2018).…”

“…We show here that KapB also upregulates autophagic flux, opposing the activity of vFLIP during viral latency. We do not yet know the precise impact of latent gene co-expression on autophagy regulation; however, the observation that latently infected B-lymphocytes displayed elevated autophagic flux suggest that a pro-autophagic phenotype dominates during KSHV latency (Pringle et al , 2019). We predict that KapB, in concert with vCyclin, promotes autophagy and that vFLIP expression works to fine tune this mechanism.…”

Targeting XPO1 enhances innate immune response and inhibits KSHV lytic replication during primary infection by nuclear stabilization of the p62 autophagy adaptor protein

“…While chemical induction of KSHV lytic replication increases autophagy in PEL cells, it is blocked at a late stage of viral replication 55 . Interestingly, KSHV inhibits autophagy by activating mTORC1 during nutrient-deprived conditions, which is important for viral replication 56 . We did not observe any LC3II and p62 changes, indicating that there was no effect on autophagy initiation and flux during the KSHV primary infection of HUVEC.…”

Autophagy in Viral Development and Progression of Cancer

“…Pringle et al have reported that mTORC1 is required for lytic replication and RTA synthesis as an activator of cellular transcription. In contrast, this autophagy inhibitor complex has not shown more significant involvement in genomic replication, late gene expression, or in the release of infectious progeny ( 338 ). Furthermore, autophagy inhibition has been reported to reduce lytic KSHV reactivation ( 339 ).…”