HIV-1 protease cleaves the serine-threonine kinases RIPK1 and RIPK2

Retrovirology

Sumit K. Chanda¹  John C. Reed³  Roland N. Wagner² 

[1] Sanford Burnham Prebys Medical Discovery Institute, 10901 North Torrey Pines Road, La Jolla, CA, USA;Department of Molecular Biology, University of Salzburg, Salzburg, Austria;Roche, Pharma Research and Early Development,Roche Innovation Center Basel, Basel, Switzerland

关键词: Proteolytic cleavage;    RIPK2;    RIPK1;    Receptor-interacting protein kinase;    HIV-1 protease;   

Others  :  1223832
DOI  :  10.1186/s12977-015-0200-6

 received in 2015-03-12, accepted in 2015-08-13,  发布年份 2015

【 摘 要 】

Background

HIV-1 protease (PR) is essential for viral infectivity as it cleaves Gag and Gag-Pol polyprotein precursors during viral maturation. Recent evidence suggests that cellular proteins can also be cleaved by PR, perhaps representing an important viral strategy to counter host defense mechanisms. Receptor-interacting protein kinase 1 (RIPK1) and RIPK2 belong to a family of serine/threonine kinases with conserved domain architecture and important functions in apoptosis, necrosis and innate immunity.

Results

We found that RIPK1 and RIPK2 but not other members of the RIP kinase family are cleaved by HIV-1 PR. In RIPK1, we identified a putative PR cleavage site; a mutation at this site rendered RIPK1 resistant to PR cleavage. RIPK1 and RIPK2 were cleaved during HIV-1 infection of T cell lines or primary activated CD4 ⁺T cells. Interfering with the viral life cycle at different stages by the addition of specific inhibitors against RT, integrase, or PR, completely prevented RIPK1 and RIPK2 cleavage. Cleavage of RIPK1 disrupted RIPK1/RIPK3 complex formation and RIPK1-mediated induction of NF-kB.

Conclusions

These findings indicate that RIPK1 and RIPK2 are targets of HIV-1 PR activity during infection, and their inactivation may contribute to modulation of cell death and host defense pathways by HIV-1.

【 授权许可】

   
2015 Wagner et al.

【 图 表 】

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