CK1δ-dependent SNAPIN dysregulation drives lysosomal failure in HIV-1 Vpr-exposed neurons: A targetable mechanism in HAND.

ABSTRACT: HIV-associated neurocognitive disorders (HANDs) persist in nearly 40% of virally suppressed individuals despite antiretroviral therapy (ART). Lysosomal dysfunction has emerged as a key contributor to HAND pathogenesis, yet the molecular mechanisms linking chronic HIV exposure to impaired neuronal degradation remain incompletely defined. Here, we identify HIV-1 viral protein R (Vpr) as a driver of lysosomal acidification failure, clustering, and degradative impairment in neurons. We report casein kinase 1 delta (CK1δ) as a central mediator of this dysfunction, acting via phosphorylation of the adapter protein SNAPIN. Vpr-induced CK1δ activation leads to hyperphosphorylation of SNAPIN, disrupting lysosomal positioning and motility. These defects are rescued by selective CK1δ inhibition, whic

SUBMITTER: Sawaya BE 

PROVIDER: S-EPMC12818168 | biostudies-literature | 2026 Feb

REPOSITORIES: biostudies-literature