Jembrana disease virus Vif antagonizes the inhibition of bovine APOBEC3 proteins through ubiquitin-mediate protein degradation

Abstract

Viral infectivity factor (Vif) encoded by lentiviruses is essential for viral replication and escaping from antiviral activity of host defensive factors APOBEC3. Jembrana disease virus (JDV) causes an acute disease syndrome with approximately 20% case fatality rate in Bali cattle. However, the interplay mechanism between JDV Vif and Bos taurus APOBEC3 (btA3) is poorly understood. In this study, we determined that JDV Vif recruits ElonginB, ElonginC(ELOB/C), Cul2 and RBX1 but without the need of CBF-β to form E3 ubiquitin ligase and induces the degradation of btA3 proteins. Further investigation identified BC-box (T149LQ151) motif required for ELOB/C binding, Cul2 box (Y167xxxxV/X172) and a zinc-binding motif (H95-C113-H115-C133) required for Cul2 binding in JDV Vif. The precise mechanism of JDV Vif overcoming the antiviral activity of btA3 proteins is helpful for the application of the broad spectrum antiviral drug targeting conserved functional domains of various species Vif proteins in the future.

CAEV Vif Hijacks ElonginB/C, CYPA and Cullin5 to Assemble the E3 Ubiquitin Ligase Complex Stepwise to Degrade oaA3Z2-Z3

“…Despite their conserved function, the cellular factors required by various lentiviruses are diverse. For example, the HIV-1 Vif hijacks Cullin5 (CUL5), ELOB/C and CBF-β to neutralize the antiviral activity of human A3 proteins (Jager et al, 2011; Zhang et al, 2011), while Cullin 2 (CUL2), ELOB/C, and RBX1, but not CUL5 or CBF-β, are used by bovine immunodeficiency virus (BIV) and Jembrana disease virus (JDV) Vif to form a CRL2 E3 ubiquitin ligase to degrade the restrictive bovine A3 proteins (Zhang W. et al, 2014; Su et al, 2018).…”

Prospects in Innate Immune Responses as Potential Control Strategies against Non-Primate Lentiviruses

“…As with sheep, cattle ( Bos taurus , Bt) encode three A3 genes: btA3Z1 , btA3Z2 , and btA3Z3 , and another splicing variant, btA3Z2Z3 [ 163 ]. Only A3Z3 and A3Z2Z3 exhibit a strong anti-lentiviral ability in in vitro cell culture systems [ 146 ] that is counteracted by the BIV and JDV Vif proteins which degrade cattle A3 proteins [ 44 ].…”

“…BIV Vif and JDV Vif are the only known retroviral proteins that can interact with CUL2 [ 164 ]. Similar to BIV, JDV Vif hijacks CUL2, ELOB/C, and RBX1, also without the need for CBF-β, to form E3 ubiquitin ligase and induce the degradation of the btA3 proteins [ 163 ].…”

“…Bovine A3Z1, as well as human and ovine counterparts, is resistant to BIV and JDV Vif-mediated degradation [ 163 , 164 ] and display no restriction on viral replication in non-myeloid cells. This result suggests that A3Z1 evolved to escape from Vif-mediated degradation, which might allow it to perform other important biological functions.…”

“…A3Z3 of gaurs ( Bos gaurus ), another bovid species living in Asia, has been shown to be resistant to JDV Vif-mediated degradation [ 44 ]. Both resistances support the coevolution of bovine and their lentiviruses [ 163 ].…”