Kaposi’s sarcoma herpesvirus activates the hypoxia response to usurp HIF2α-dependent translation initiation for replication and oncogenesis

MÉNDEZ-SOLÍS, OMAYRA; BENDJENNAT, MOURAD; NAIPAUER, JULIAN; THEODORIDIS, PHAEDRA R.; HO, J.J. DAVID; VERDUN, RAMIRO E.; HARE, JOSHUA M.; CESARMAN, ETHEL; LEE, STEPHEN; MESRI, ENRIQUE A.

Cell Reports

cell press

Año: 2021 vol. 37

2211-1247

Kaposi?s sarcoma herpesvirus (KSHV) is an angiogenesis-inducing oncovirus whose ability to usurp the oxygen-sensingmachinery is central to its oncogenicity. By upregulating the hypoxia-inducible factors (HIFs),KSHV reprograms infected cells to a hypoxia-like state, triggering angiogenesis. Here we identify a link betweenKSHV replicative biology and oncogenicity by showing that KSHV?s ability to regulate HIF2a levels andlocalization to the endoplasmic reticulum (ER) in normoxia enables translation of viral lytic mRNAs throughthe HIF2a-regulated eIF4E2 translation-initiation complex. This mechanism of translation in infected cellsis critical for lytic protein synthesis and contributes to KSHV-induced PDGFRA activation and VEGF secretion.Thus, KSHV regulation of the oxygen-sensing machinery allows virally infected cells to initiate translationvia the mTOR-dependent eIF4E1 or the HIF2a-dependent, mTOR-independent, eIF4E2. This ??translationinitiation plasticity?? (TRIP) is an oncoviral strategy used to optimize viral protein expression that links molecularstrategies of viral replication to angiogenicity and oncogenesis.