Primary Cilia-Mediated Hedgehog Signaling Regulates Cell Fate During ER Stress-Induced Life or Death Decisions

Primary cilia play critical roles in development and physiology. The unfolded protein response (UPR), triggered by endoplasmic reticulum (ER) stress, is a fundamental cellular process. However, whether and how ER stress influences ciliary assembly and function remain poorly understood. Here, we demonstrate that ER stress promotes ciliogenesis and hedgehog (HH) signaling by upregulating cholesterol levels, thereby alleviating cellular damage. IRE1 and PERK, sensors of ER stress, positively regulate ciliogenesis by enhancing the trafficking of preciliary vesicles through upregulation of cellular cholesterol levels via activation of SREBP2. Furthermore, the cholesterol content in the ciliary membrane also increases during ER stress, leading to enhanced ciliary recruitment of Smoothened (SMO) and activation of HH signaling. The activation of HH signaling via primary cilium is crucial for protecting cells from stress-induced damage. Our findings unveil a pivotal role of cilia-mediated hedgehog signaling in cell fate determination under ER stress.