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

作者：Yuwen Chen, Jiaxin Lin, Zongyou Zou, Zuo‐Qin Yan, Ruizhe Qian, Chao Lü, Bingxuan Hua · 发表于：FEBS Letters · 年份：2026 · DOI：10.1002/1873-3468.70291 · 被引用次数：2 · 研究领域：Circadian rhythm and melatonin、Endoplasmic Reticulum Stress and Disease、Light effects on plants

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.