ERLIN2 –Ca 2+ – CREB signaling coordinates circadian timing via CRY1 / CRY2 feedback

Circadian regulation in peripheral cells depends on calcium dynamics, but the upstream mechanisms remain unclear. We identify endoplasmic reticulum lipid raft‐associated protein 2 (ERLIN2) as a regulator of the peripheral clock. Knockdown and overexpression of ERLIN2 in C2C12 skeletal muscle cells show that ERLIN2 positively regulates cryptochrome circadian regulator 1/2 (CRY1/2) transcription and maintains rhythmicity. ERLIN2 regulates inositol 1,4,5‐trisphosphate receptor (IP 3 R)‐mediated Ca 2+ release and activates the calcium/calmodulin‐dependent protein kinase II (CaMKII) – mitogen‐activated protein kinase (MAPK) – cAMP response element‐binding protein (CREB) pathway. ATP induced IP 3 R‐dependent Ca 2+ transients, CREB phosphorylation, and Per1 expression, reshaping circadian rhythm, effects blocked by IP 3 R, Ca 2+ , or CaMKII inhibition. CRY1 enhances and CRY2 suppresses CREB signaling, establishing a feedback loop with ERLIN2. This ERLIN2–Ca 2+ –CREB–CRY1/2 axis couples membrane contact sites to circadian regulation. Impact statement This study reveals ERLIN2 as a key regulator linking calcium signaling to circadian rhythms, establishing an ERLIN2–Ca 2+ –CREB–CRY1/2 axis that advances understanding of cellular clock control.