Kolapalli Srinivasa P, Beese Carsten J, Reid Steven E, Brynjólfsdóttir Sólveig H, Jørgensen Maria H, Jain Ashish, Cuenco Joyceline, Lewinska Monika, Abdul-Al Ahmad, López Aida R, Jäättelä Marja, Sakamoto Kei, Andersen Jesper B, Maeda Kenji, Rusten Tor E, Lund Anders H, Frankel Lisa B
Cellular Homeostasis and Recycling, Danish Cancer Institute, DK-2100 Copenhagen, Denmark.
Biotech Research and Innovation Centre, Faculty of Health and Medical Sciences, University of Copenhagen, DK-2200 Copenhagen, Denmark.
Sci Adv. 2025 Jan 17;11(3):eadr2450. doi: 10.1126/sciadv.adr2450.
Nutrient deprivation is a major trigger of autophagy, a conserved quality control and recycling process essential for cellular and tissue homeostasis. In a high-content image-based screen of the human ubiquitome, we here identify the E3 ligase Pellino 3 (PELI3) as a crucial regulator of starvation-induced autophagy. Mechanistically, PELI3 localizes to autophagic membranes, where it interacts with the ATG8 proteins through an LC3-interacting region (LIR). This facilitates PELI3-mediated ubiquitination of ULK1, driving ULK1's subsequent proteasomal degradation. PELI3 depletion leads to an aberrant accumulation and mislocalization of ULK1 and disrupts the early steps of autophagosome formation. Genetic deletion of Peli3 in mice impairs fasting-induced autophagy in the liver and enhances starvation-induced hepatic steatosis by reducing autophagy-mediated clearance of lipid droplets. Notably, PELI3 expression is decreased in the livers of patients with metabolic dysfunction-associated steatotic liver disease (MASLD), suggesting its role in hepatic steatosis development in humans. The findings suggest that PELI3-mediated control of autophagy plays a protective role in liver health.
营养剥夺是自噬的主要触发因素，自噬是一种保守的质量控制和循环过程，对细胞和组织稳态至关重要。在一项基于高内涵图像的人类泛素组筛选中，我们在此确定E3连接酶Pellino 3（PELI3）是饥饿诱导自噬的关键调节因子。从机制上讲，PELI3定位于自噬膜，在那里它通过LC3相互作用区域（LIR）与ATG8蛋白相互作用。这促进了PELI3介导的ULK1泛素化，驱动ULK1随后的蛋白酶体降解。PELI3的缺失导致ULK1异常积累和定位错误，并破坏自噬体形成的早期步骤。小鼠中Peli3的基因缺失会损害肝脏中禁食诱导的自噬，并通过减少自噬介导的脂滴清除来加重饥饿诱导的肝脂肪变性。值得注意的是，代谢功能障碍相关脂肪性肝病（MASLD）患者肝脏中PELI3的表达降低，表明其在人类肝脂肪变性发展中的作用。这些发现表明，PELI3介导的自噬调控对肝脏健康起到保护作用。
