Association with PAK2 enables functional interactions of lentiviral nef proteins with the exocyst complex

Research output: Contribution to journalResearch articleContributedpeer-review

Contributors

  • Andrea Imle - (Author)
  • Libin Abraham - (Author)
  • Nikolaos Tsopoulidis - (Author)
  • Bernard Hoflack - , Chair of Proteomics (Author)
  • Kalle Saksela - (Author)
  • Oliver T. Facklera - (Author)

Abstract

Human immunodeficiency virus type 1 (HIV-1) Nef enhances virus replication and contributes to immune evasion in vivo, but the underlying molecular mechanisms remain incompletely defined. Nef interferes with host cell actin dynamics to restrict T lymphocyte responses to chemokine stimulation and T cell receptor engagement. This relies on the assembly of a labile multiprotein complex including the host kinase PAK2 that Nef usurps to phosphorylate and inactivate the actin-severing factor cofilin. Components of the exocyst complex (EXOC), an octameric protein complex involved in vesicular transport and actin remodeling, were recently reported to interact with Nef via the same molecular surface that mediates PAK2 association. Exploring the functional relevance of EXOC in Nef-PAK2 complex assembly/function, we found Nef-EXOC interactions to be specifically mediated by the PAK2 interface of Nef, to occur in infected human T lymphocytes, and to be conserved among lentiviral Nef proteins. In turn, EXOC was dispensable for direct downstream effector functions of Nef-associated PAK2. Surprisingly, PAK2 was essential for Nef-EXOC association, which required a functional Rac1/Cdc42 binding site but not the catalytic activity of PAK2. EXOC was dispensable for Nef functions in vesicular transport but critical for inhibition of actin remodeling and proximal signaling upon T cell receptor engagement. Thus, Nef exploits PAK2 in a stepwise mechanism in which its kinase activity cooperates with an adaptor function for EXOC to inhibit host cell actin dynamics.

Details

Original languageEnglish
Article numbere01309-15
JournalMBio
Volume6
Issue number5
Publication statusPublished - 2015
Peer-reviewedYes

External IDs

PubMed 26350970

Keywords

Sustainable Development Goals

ASJC Scopus subject areas