Novel Host Protein TBC1D16, a GTPase Activating Protein of Rab5C, Inhibits Prototype Foamy Virus Replication.

Jun Yan,Zhi Li,Song Han,Yan Sun,Xiaohua He,Shanshan Wang,Wanhong Liu,Yingcheng Zheng,Peipei Yuan,Biwen Peng,Jun Yin

doi:10.3389/fimmu.2021.658660

Abstract

Prototype foamy virus (PFV) is a member of the oldest family of retroviruses and maintains lifelong latent infection in the host. The lifelong latent infection of PFV may be maintained by the restriction factors of viral replication in the host. However, the mechanisms involved in PFV latent infection are poorly understood. Here, we found that TBC1D16, a TBC domain-containing protein, is significantly down-regulated after PFV infection. Tre2/Bub2/Cdc16 (TBC) domain-containing proteins function as Rab GTPase-activating proteins (GAPs) and are participates in the progression of some diseases and many signaling pathways. However, whether TBC proteins are involved in PFV replication has not been determined. Here, we found that TBC1D16 is a novel antiviral protein that targets Rab5C to suppress PFV replication. Overexpression TBC1D16 inhibited the transcription and expression of Tas and Gag, and silencing TBC1D16 enhanced the PFV replication. Moreover, the highly conserved amino acid residues R494 and Q531 in the TBC domain of TBC1D16 were essential for inhibiting PFV replication. We also found that TBC1D16 promoted the production of PFV-induced IFN-β and the transcription of downstream genes. These results suggest that TBC1D16 might be the first identified TBC proteins that inhibited PFV replication and the mechanism by which TBC1D16 inhibited PFV replication could provide new insights for PFV latency.

Highlights

Foamy viruses (FVs; known as spumaviruses) are christened because they induce the endoplasmic reticulum forming voids and produce foam-like lesions when these viruses replicate in adherent cell cultures of epithelial or fibroblastoid origin [1]
We found that TBC1D16 is a GTPase-activating proteins (GAPs) of Rab5C and inhibits prototype foamy virus (PFV) replication by interacting with Rab5C
These results showed that the expression of TBC1D16 was significantly down-regulated in PFV-infected HEK293T cells

Summary

Introduction

Foamy viruses (FVs; known as spumaviruses) are christened because they induce the endoplasmic reticulum forming voids and produce foam-like lesions when these viruses replicate in adherent cell cultures of epithelial or fibroblastoid origin [1]. PFV has an internal promoter (IP) in the coding region of the Env protein that directs the expression of the accessory proteins genes Tas and Bet [5]. As a DNA binding protein, Tas binds to the LTR and IP promoters of PFV activating and regulating the transcription and replication of the virus [7]. Gag has high affinity with DNA and RNA, with a nuclear localization signal, and participates in the process of viral gene reverse transcription and host gene integration [12]. These characteristics are quite different from those of other retroviruses and could be key factors in PFV latent infection and nonpathogenicity

Methods

Results

Conclusion