Zhuang Yixiao, Zhang Xinyi, Zhang Shuang, Sun Yunpeng, Wang Hui, Chen Yuxuan, Zhang Hanyin, Zou Penglai, Feng Yonghao, Lu Xiaodan, Chen Peijie, Xu Yi, Li John Zhong, Gao Huanqing, Jin Li, Kong Xingxing
State Key Laboratory of Genetic Engineering, School of Life Sciences, Fudan University, Shanghai, 200438, China.
Interdisciplinary Research Center on Biology and Chemistry, Shanghai Institute of Organic Chemistry, Chinese Academy of Sciences, Shanghai, 201210, China.
Nat Commun. 2025 May 14;16(1):4455. doi: 10.1038/s41467-025-59618-0.
Thermogenic proteins are down-regulated under thermal stress, including PGC1α· However, the molecular mechanisms are not fully understood. Here, we addressed that chaperone-mediated autophagy could regulate the stability of PGC1α under thermal stress. In mice, knockdown of Lamp2a, one of the two components of CMA, in BAT showed increased PGC1α protein and improved metabolic phenotypes. Combining the proteomics of brown adipose tissue (BAT), structure prediction, co-immunoprecipitation- mass spectrum and biochemical assays, we found that PARK7, a Parkinson's disease causative protein, could sense the temperature changes and interact with LAMP2A and HSC70, respectively, subsequently manipulate the activity of CMA. Knockout of Park7 specific in BAT promoted BAT whitening, leading to impaired insulin sensitivity and energy expenditure at thermoneutrality. Moreover, inhibiting the activity of CMA by knockdown of LAMP2A reversed the effects induced by Park7 ablation. These findings suggest CMA is required for BAT to sustain thermoneutrality-induced whitening through degradation of PGC1α.
产热蛋白在热应激下会下调，包括PGC1α。然而，其分子机制尚未完全阐明。在此，我们探讨了伴侣介导的自噬可在热应激下调节PGC1α的稳定性。在小鼠中，敲低褐色脂肪组织（BAT）中分子伴侣介导的自噬（CMA）两个组成成分之一的Lamp2a，可使PGC1α蛋白增加并改善代谢表型。结合褐色脂肪组织的蛋白质组学、结构预测、免疫共沉淀-质谱和生化分析，我们发现帕金森病致病蛋白PARK7可感知温度变化，并分别与LAMP2A和HSC70相互作用，随后调控CMA的活性。特异性敲除BAT中的Park7会促进BAT变白，导致体温中性条件下胰岛素敏感性受损和能量消耗减少。此外，通过敲低LAMP2A抑制CMA的活性可逆转Park7缺失所诱导的效应。这些发现表明，CMA是BAT通过降解PGC1α维持体温中性诱导的BAT变白所必需的。
