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

• Published in: Cell 2015-06, Vol.161 (6), p.1293-1305
• Main Authors: Yoh, Sunnie M., Schneider, Monika, Seifried, Janna, Soonthornvacharin, Stephen, Akleh, Rana E., Olivieri, Kevin C., De Jesus, Paul D., Ruan, Chunhai, de Castro, Elisa, Ruiz, Pedro A., Germanaud, David, des Portes, Vincent, García-Sastre, Adolfo, König, Renate, Chanda, Sumit K.
• Format: Article
• Language: English
• Subjects: Base Sequence; Carrier Proteins - metabolism; Cell Line; Cerebral Palsy - immunology; DNA, Viral - genetics; DNA-Binding Proteins; HIV-1 - immunology; HIV-1 - physiology; Humans; Immunity, Innate; Mental Retardation, X-Linked - immunology; Molecular Sequence Data; Nuclear Proteins - metabolism; Nucleotidyltransferases - metabolism
• ISSN: 0092-8674; 1097-4172
• DOI: 10.1016/j.cell.2015.04.050

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. [Display omitted] •PQBP1 is an essential component of cGAS/IRF3-dependent innate response to HIV•PQBP1 directly binds to immunogenic reverse-transcribed HIV-1 DNA•PQBP1 physically associates with and regulates cGAS activity•Renpenning patients’ cells have an impaired innate immune response to HIV-1 Polyglutamine binding protein 1 (PQBP1) is a sensor of HIV-1 infection, directly binding to reverse-transcribed HIV-1 DNA and interacting with cGAS to initiate an IRF3-dependent innate response in dendritic cells.