PQBP1 Is a Proximal Sensor of the cGAS-Dependent Innate Response to HIV-1

Cell. 2015 Jun 4;161(6):1293-1305. doi: 10.1016/j.cell.2015.04.050.

Abstract

Dendritic cells (DCs) play a critical role in the immune response to viral infection through the facilitation of cell-intrinsic antiviral activity and the activation of adaptive immunity. HIV-1 infection of DCs triggers an IRF3-dependent innate immune response, which requires the activity of cyclic GAMP synthase (cGAS). We report the results of a targeted RNAi screen utilizing primary human monocyte-derived DCs (MDDCs) to identify immune regulators that directly interface with HIV-1-encoded features to initiate this innate response. Polyglutamine binding protein 1 (PQBP1) emerged as a strong candidate through this analysis. We found that PQBP1 directly binds to reverse-transcribed HIV-1 DNA and interacts with cGAS to initiate an IRF3-dependent innate response. MDDCs derived from Renpenning syndrome patients, who harbor mutations in the PQBP1 locus, possess a severely attenuated innate immune response to HIV-1 challenge, underscoring the role of PQBP1 as a proximal innate sensor of a HIV-1 infection.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Base Sequence
  • Carrier Proteins / metabolism*
  • Cell Line
  • Cerebral Palsy / immunology
  • DNA, Viral / genetics
  • HIV-1 / immunology*
  • HIV-1 / physiology
  • Humans
  • Immunity, Innate*
  • Mental Retardation, X-Linked / immunology
  • Molecular Sequence Data
  • Nuclear Proteins / metabolism*
  • Nucleotidyltransferases / metabolism*

Substances

  • Carrier Proteins
  • DNA, Viral
  • Nuclear Proteins
  • PQBP1 protein, human
  • MB21D1 protein, human
  • Nucleotidyltransferases

Supplementary concepts

  • Renpenning syndrome 1