bims-lypmec 2025-01-26 papers

Autophagy. 2025 Jan 21.

Induction of lysosome biogenesis is a novel function of the CGAS-STING1 pathway.

Induction of macroautophagy/autophagy has been established as an important function elicited by the CGAS-STING1 pathway during pathogen infection. However, it remains unknown whether lysosomal activity within the cell in these settings is concurrently enhanced to cope with the increased autophagic flux. Recently, we discovered that the CGAS-STING1 pathway elevates the degradative capacity of the cell by activating lysosome biogenesis. Intriguingly, we found that STING1-induced GABARAP lipidation, rather than TBK1 activation, serves as the key mediator triggering the nuclear translocation of transcription factor TFEB and enhances the expression of lysosome-related genes. Mechanistically, we demonstrated that lipidated GABARAP on single membranes, regulated by the V-ATPase-ATG16L1 axis, sequesters the FLCN-FNIP complex to abolish its function toward RRAGC-RRAGD, leading to a specific impairment of MTORC1-dependent phosphorylation of TFEB and resulting in its subsequent nuclear translocation. Functionally, we showed that STING1-induced lysosome biogenesis is essential for the clearance of cytoplasmic DNA and the elimination of invading pathogens. Collectively, our findings underscore the induction of lysosome biogenesis as a novel function of the CGAS-STING1 pathway.China; Yinfeng Xu; Email: yinfengxu@hnfnu.edu.cn; Hunan First Normal University, 1015 Feng-Lin-San Road, Changsha, Hunan 410,205, China.

Keywords: Autophagy; CGAS; GABARAP; STING1; TFEB; lysosome

DOI: https://doi.org/10.1080/15548627.2025.2456064

Nat Struct Mol Biol. 2025 Jan 17.

Molecular architecture of human LYCHOS involved in lysosomal cholesterol signaling.

Qi Xiong, Zhini Zhu, Tingting Li, Xiaotian Li, Zixuan Zhou, Yulin Chao, Chuanhui Yang, Suihan Feng, Qianhui Qu, Dianfan Li.

Lysosomal membrane protein LYCHOS (lysosomal cholesterol signaling) translates cholesterol abundance to mammalian target of rapamycin activation. Here we report the 2.11-Å structure of human LYCHOS, revealing a unique fusion architecture comprising a G-protein-coupled receptor (GPCR)-like domain and a transporter domain that mediates homodimer assembly. The NhaA-fold transporter harbors a previously uncharacterized intramembrane Na+ pocket. The GPCR-like domain is stabilized, by analogy to canonical GPCRs, in an inactive state through 'tethered antagonism' by a lumenal loop and strong interactions at the cytosol side preventing the hallmark swing of the sixth transmembrane helix seen in active GPCRs. A cholesterol molecule and an associated docosahexaenoic acid (DHA)-phospholipid are entrapped between the transporter and GPCR-like domains, with the DHA-phospholipid occupying a pocket previously implicated in cholesterol sensing, indicating inter-domain coupling via dynamic lipid-protein interactions. Our work provides a high-resolution framework for functional investigations of the understudied LYCHOS protein.

DOI: https://doi.org/10.1038/s41594-024-01474-5

Science. 2025 Jan 24. 387(6732): 359-361

Decoding lysosome communication.

Soni Savai Pullamsetti, Rajkumar Savai.

Lysosome interaction with other organelles may be linked to pulmonary hypertension.

DOI: https://doi.org/10.1126/science.adv1201

Nat Struct Mol Biol. 2025 Jan 17.

Cryo-EM reveals cholesterol binding in the lysosomal GPCR-like protein LYCHOS.

Jie Zhao, Qingya Shen, Xihao Yong, Xin Li, Xiaowen Tian, Suyue Sun, Zheng Xu, Xiaoyu Zhang, Lu Zhang, Hao Yang, Zhenhua Shao, Haoxing Xu, Yiyang Jiang, Yan Zhang, Wei Yan.

Cholesterol plays a pivotal role in modulating the activity of mechanistic target of rapamycin complex 1 (mTOR1), thereby regulating cell growth and metabolic homeostasis. LYCHOS, a lysosome-localized G-protein-coupled receptor-like protein, emerges as a cholesterol sensor and is capable of transducing the cholesterol signal to affect the mTORC1 function. However, the precise mechanism by which LYCHOS recognizes cholesterol remains unknown. Here, using cryo-electron microscopy, we determined the three-dimensional structural architecture of LYCHOS in complex with cholesterol molecules, revealing a unique arrangement of two sequential structural domains. Through a comprehensive analysis of this structure, we elucidated the specific structural features of these two domains and their collaborative role in the process of cholesterol recognition by LYCHOS.

DOI: https://doi.org/10.1038/s41594-024-01470-9

Circulation. 2025 Jan 21. 151(3): 199-201

SGLT Inhibitors in Persons With Heart Failure and Type 1 Diabetes: Filling the Therapeutic Gap.

Ify R Mordi, Rory J McCrimmon, Chim C Lang.

Keywords: clinical trials as topic; diabetes mellitus, type 1; diabetes mellitus, type 2; heart failure; sodium-glucose transporter 2 inhibitors

DOI: https://doi.org/10.1161/CIRCULATIONAHA.124.069695

Science. 2025 Jan 24. 387(6732): eadn7277

Lysosomal dysfunction and inflammatory sterol metabolism in pulmonary arterial hypertension.

Vascular inflammation regulates endothelial pathophenotypes, particularly in pulmonary arterial hypertension (PAH). Dysregulated lysosomal activity and cholesterol metabolism activate pathogenic inflammation, but their relevance to PAH is unclear. Nuclear receptor coactivator 7 (NCOA7) deficiency in endothelium produced an oxysterol and bile acid signature through lysosomal dysregulation, promoting endothelial pathophenotypes. This oxysterol signature overlapped with a plasma metabolite signature associated with human PAH mortality. Mice deficient for endothelial Ncoa7 or exposed to an inflammatory bile acid developed worsened PAH. Genetic predisposition to NCOA7 deficiency was driven by single-nucleotide polymorphism rs11154337, which alters endothelial immunoactivation and is associated with human PAH mortality. An NCOA7-activating agent reversed endothelial immunoactivation and rodent PAH. Thus, we established a genetic and metabolic paradigm that links lysosomal biology and oxysterol processes to endothelial inflammation and PAH.

DOI: https://doi.org/10.1126/science.adn7277