PCID2 dysregulates transcription and viral RNA processing to promote HIV-1 latency

HIV-1 latency results from tightly regulated molecular processes that act at distinct steps of HIV-1 gene expression. Here, we characterize PCI domain-containing 2 (PCID2) protein, a subunit of the transcription and export complex 2 (TREX2) complex, to enforce transcriptional repression and post-tra...

Full description

Saved in:

Bibliographic Details
Published in:	iScience Vol. 27; no. 3; p. 109152
Main Authors:	Crespo, Raquel, Ne, Enrico, Reinders, Julian, Meier, Jenny I.J., Li, Chengcheng, Jansen, Sanne, Górska, Alicja, Koçer, Selin, Kan, Tsung Wai, Doff, Wouter, Dekkers, Dick, Demmers, Jeroen, Palstra, Robert-Jan, Rao, Shringar, Mahmoudi, Tokameh
Format:	Journal Article
Language:	English
Published:	United States Elsevier Inc 15-03-2024 Elsevier
Subjects:	Cell biology Virology Cell biology Virology
Online Access:	Get full text
Tags:	Add Tag No Tags, Be the first to tag this record!

Description
Summary:	HIV-1 latency results from tightly regulated molecular processes that act at distinct steps of HIV-1 gene expression. Here, we characterize PCI domain-containing 2 (PCID2) protein, a subunit of the transcription and export complex 2 (TREX2) complex, to enforce transcriptional repression and post-transcriptional blocks to HIV-1 gene expression during latency. PCID2 bound the latent HIV-1 LTR (long terminal repeat) and repressed transcription initiation during latency. Depletion of PCID2 remodeled the chromatin landscape at the HIV-1 promoter and resulted in transcriptional activation and latency reversal. Immunoprecipitation coupled to mass spectrometry identified PCID2-interacting proteins to include negative viral RNA (vRNA) splicing regulators, and PCID2 depletion resulted in over-splicing of intron-containing vRNA in cell lines and primary cells obtained from PWH. MCM3AP and DSS1, two other RNA-binding TREX2 complex subunits, also inhibit transcription initiation and vRNA alternative splicing during latency. Thus, PCID2 is a novel HIV-1 latency-promoting factor, which in context of the TREX2 sub-complex PCID2-DSS1-MCM3AP blocks transcription and dysregulates vRNA processing. [Display omitted] •PCID2 is bound to the latent HIV-1 LTR as a transcriptional repressor•PCID2 enforces latency by acting on transcription initiation•PCID2 establishes blocks to alternative splicing during HIV-1 latency•PCID2 misregulates alternative splicing in cells obtained from people with HIV-1 Virology; Cell biology
Bibliography:	ObjectType-Article-1 SourceType-Scholarly Journals-1 ObjectType-Feature-2 content type line 23 Lead contact
ISSN:	2589-0042 2589-0042
DOI:	10.1016/j.isci.2024.109152