UFMylation of BiP / GRP78 Is Crucial for Maintenance of Endoplasmic Reticulum Homeostasis

作者：Li Zhu, Qian Liang, Yanmin Guo, Yaxiang Wang, Miao Wang, Yu‐Sheng Cong · 发表于：The FASEB Journal · 年份：2025 · DOI：10.1096/fj.202500976rr · 被引用次数：5 · 研究领域：Endoplasmic Reticulum Stress and Disease、Photosynthetic Processes and Mechanisms、RNA regulation and disease

UFMylation is essential for the embryonic development of metazoans and is associated with several human diseases. Accumulating evidence indicates that the UFMylation pathway plays a critical role in the maintenance of endoplasmic reticulum (ER) homeostasis. However, the underlying mechanisms and relevant cellular targets remain largely unknown. Here, we report that the ER chaperone protein BiP can be covalently modified by UFM1 at lysine residues 294, 296, 352, 353, and 370. This modification destabilizes BiP by promoting its ubiquitination and subsequent proteasome degradation. Depletion of the UFM1 E3 ligase UFL1 or mutation of the BiP UFMylation sites impairs BiP's functions as an ER chaperone and ER stress sensor, thereby increasing apoptotic cell death under ER stress. Our findings suggest that the UFMylation of BiP is critical for maintaining ER homeostasis.