The RNA-binding protein RBM39 scaffolds an m⁶A-dependent RNA decay complex that destabilizes Tat transcripts and restricts HIV-1 reactivation.

ABSTRACT: The persistence of latent HIV-1 reservoirs remains a critical barrier to functional curing AIDS, as current latency-reversing agents (LRAs) exhibit limited clinical efficacy. While RNA modifications like N⁶-methyladenosine (m⁶A) regulate viral replication, their role in maintaining HIV-1 latency is poorly defined. Here, we identify the RNA-binding protein RBM39 as a scaffold organizing an m⁶A-dependent silencing complex that enforces viral latency. Through proteomic and functional analyses, we demonstrate that RBM39 recruits the m⁶A reader YTHDC1 and the RNA helicase DDX5, forming a tripartite complex that accelerates Tat RNA decay and enforces viral quiescence. Genetic or pharmacological degradation of RBM39 (using the clinically explored molecular glue indisulam) potently reactivates lat

SUBMITTER: Deng X 

PROVIDER: S-EPMC12617877 | biostudies-literature | 2025 Nov

REPOSITORIES: biostudies-literature