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

Kaposi’s sarcoma herpesvirus (KSHV) is an angiogenesis-inducing oncovirus whose ability to usurp the oxygen-sensing machinery 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 between KSHV replicative biology and oncogenicity by showing that KSHV's ability to regulate HIF2α levels and localization to the endoplasmic reticulum (ER) in normoxia enables translation of viral lytic mRNAs through the HIF2α-regulated eIF4E2 translation-initiation complex. This mechanism of translation in infected cells is 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 translation via the mTOR-dependent eIF4E1 or the HIF2α-dependent, mTOR-independent, eIF4E2. This “translation initiation plasticity” (TRIP) is an oncoviral strategy used to optimize viral protein expression that links molecular strategies of viral replication to angiogenicity and oncogenesis. [Display omitted] •KSHV upregulates and localizes HIF2α to the ER in normoxia for a translational role•KSHV mRNAs are bound and translated by the eIF4E2/HIF2α-containing complex eIF4FH•eIF4FH contributes to translation of KSHV-induced sarcomagenic proteins•KSHV-infected cells translate proteins via mTOR-dependent or -independent mechanisms Méndez-Solís et al. show that KSHV during the lytic phase upregulates and re-localizes HIF2α to the ER to gain access to the alternative translation machinery eIF4FH. This KSHV “translation initiation plasticity” allows infected cells to translate viral and host proteins via mTOR-dependent or -independent mechanisms contributing to KSHV-induced sarcomagenesis.