title: HIV-1 protease cleaves the serine-threonine kinases RIPK1 and RIPK2.
abstract: 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.
authors: Sanford Burnham Prebys Medical Discovery Institute, 10901 North Torrey Pines Road, La Jolla, CA, USA. rwagner@sbpdiscovery.org.|Department of Molecular Biology, University of Salzburg, Salzburg, Austria. rwagner@sbpdiscovery.org.
authors: Roland N
authors: RN
authors: Wagner
authors: Sanford Burnham Prebys Medical Discovery Institute, 10901 North Torrey Pines Road, La Jolla, CA, USA. john_c.reed@roche.com.|Roche, Pharma Research and Early Development, Roche Innovation Center Basel, Basel, Switzerland. john_c.reed@roche.com.
authors: John C
authors: JC
authors: Reed
authors: Sanford Burnham Prebys Medical Discovery Institute, 10901 North Torrey Pines Road, La Jolla, CA, USA. schanda@sbpdiscovery.org.
authors: Sumit K
authors: SK
authors: Chanda
mesh_terms: D015496:CD4-Positive T-Lymphocytes / Q000821:virology; D016923:Cell Death; D002478:Cells, Cultured; D057809:HEK293 Cells; D016333:HIV Protease / Q000378:metabolism*; D015497:HIV-1 / Q000187:drug effects / Q000201:enzymology* / Q000254:growth & development / Q000502:physiology; D006801:Humans; D019169:Jurkat Cells; D016328:NF-kappa B / Q000378:metabolism; D053475:Receptor-Interacting Protein Serine-Threonine Kinase 2 / Q000235:genetics / Q000378:metabolism*; D053422:Receptor-Interacting Protein Serine-Threonine Kinases / Q000235:genetics / Q000378:metabolism*
chemical_list: D016328:NF-kappa B; C506249:RIPK1 protein, human; C506253:RIPK2 protein, human; C119705:RIPK3 protein, human; D053475:Receptor-Interacting Protein Serine-Threonine Kinase 2; D053422:Receptor-Interacting Protein Serine-Threonine Kinases; D016333:HIV Protease; C514803:p16 protease, Human immunodeficiency virus 1