β-arrestin1 orchestrates endosomal signaling to regulate translational control of circadian light entrainment

In mammals, circadian entrainment relies on signaling pathways that translate light input into molecular changes within the central pacemaker, the suprachiasmatic nucleus (SCN). Here, using β‑arrestin1 (ARRB1)-deficient mice, we identify a critical role for β‑arrestin1 in this process, showing that endosomal signaling underlies key steps in clock resetting. We demonstrate that ARRB1 is required for PAC1 receptor internalization and for the activation of endosomal signaling in response to light or PACAP. ARRB1‑dependent PAC1 endosomal signaling activates an ERK1/2-RSK1-S6 cascade that enhances protein translation and contributes to the induction of PER proteins. Transcriptional responses remain intact, underscoring the spatial specificity of ARRB1 function. Our findings position endosomes as critical subcellular hubs for circadian signal transduction and reveal a non-canonical, β-arrestin1-dependent entrainment mechanism that operates through translational control. Together, these results challenge traditional GPCR signaling paradigms and establish endosome-based signaling as a key regulator of circadian timekeeping. β arrestin1-mediated endosomal GPCR signaling is shown to be a crucial component of light-induced entrainment of the central circadian clock in mammals. Reppert, S. M. & Weaver, D. R. Coordination of circadian timing in mammals. Na ture 418, 935–941 (2002). Golombek, D. A. & Rosenstein, R. E. Physiology of circadian entrainment. Physiol. Rev. 90, 1063–1102 (2010). Mendoza-Viveros, L. et al. Molecular... [12886 chars]