bims-lypmec 2023-11-19 papers

Nat Commun. 2023 Nov 13. 14(1): 7338

Local membrane source gathering by p62 body drives autophagosome formation.

Xuezhao Feng, Daxiao Sun, Yanchang Li, Jinpei Zhang, Shiyu Liu, Dachuan Zhang, Jingxiang Zheng, Qing Xi, Haisha Liang, Wenkang Zhao, Ying Li, Mengbo Xu, Jiayu He, Tong Liu, Ayshamgul Hasim, Meisheng Ma, Ping Xu, Na Mi.

Autophagosomes are double-membrane vesicles generated intracellularly to encapsulate substrates for lysosomal degradation during autophagy. Phase separated p62 body plays pivotal roles during autophagosome formation, however, the underlying mechanisms are still not fully understood. Here we describe a spatial membrane gathering mode by which p62 body functions in autophagosome formation. Mass spectrometry-based proteomics reveals significant enrichment of vesicle trafficking components within p62 body. Combining cellular experiments and biochemical reconstitution assays, we confirm the gathering of ATG9 and ATG16L1-positive vesicles around p62 body, especially in Atg2ab DKO cells with blocked lipid transfer and vesicle fusion. Interestingly, p62 body also regulates ATG9 and ATG16L vesicle trafficking flux intracellularly. We further determine the lipid contents associated with p62 body via lipidomic profiling. Moreover, with in vitro kinase assay, we uncover the functions of p62 body as a platform to assemble ULK1 complex and invigorate PI3KC3-C1 kinase cascade for PI3P generation. Collectively, our study raises a membrane-based working model for multifaceted p62 body in controlling autophagosome biogenesis, and highlights the interplay between membraneless condensates and membrane vesicles in regulating cellular functions.

DOI: https://doi.org/10.1038/s41467-023-42829-8

Nature. 2023 Nov 15.

Stress granules plug and stabilize damaged endolysosomal membranes.

Claudio Bussi, Agustín Mangiarotti, Christian Vanhille-Campos, Beren Aylan, Enrica Pellegrino, Natalia Athanasiadi, Antony Fearns, Angela Rodgers, Titus M Franzmann, Anđela Šarić, Rumiana Dimova, Maximiliano G Gutierrez.

Endomembrane damage represents a form of stress that is detrimental for eukaryotic cells1,2. To cope with this threat, cells possess mechanisms that repair the damage and restore cellular homeostasis3-7. Endomembrane damage also results in organelle instability and the mechanisms by which cells stabilize damaged endomembranes to enable membrane repair remains unknown. Here, by combining in vitro and in cellulo studies with computational modelling we uncover a biological function for stress granules whereby these biomolecular condensates form rapidly at endomembrane damage sites and act as a plug that stabilizes the ruptured membrane. Functionally, we demonstrate that stress granule formation and membrane stabilization enable efficient repair of damaged endolysosomes, through both ESCRT (endosomal sorting complex required for transport)-dependent and independent mechanisms. We also show that blocking stress granule formation in human macrophages creates a permissive environment for Mycobacterium tuberculosis, a human pathogen that exploits endomembrane damage to survive within the host.

DOI: https://doi.org/10.1038/s41586-023-06726-w

Autophagy. 2023 Nov 14. 1-4

Ups and downs of lysosomal pH: conflicting roles of LAMP proteins?

Jonathan Handy, Gustavo C Macintosh, Andreas Jenny.

The acidic pH of lysosomes is critical for catabolism in eukaryotic cells and is altered in neurodegenerative disease including Alzheimer and Parkinson. Recent reports using Drosophila and mammalian cell culture systems have identified novel and, at first sight, conflicting roles for the lysosomal associated membrane proteins (LAMPs) in the regulation of the endolysosomal system.Abbreviation: AD: Alzheimer disease; LAMP: lysosomal associated membrane protein; LTR: LysoTracker; PD: Parkinson disease; TMEM175: transmembrane protein 175; V-ATPase: vacuolar-type H+-translocating ATPase.

Keywords: Alzheimer; Autophagy; LAMP proteins; Parkinson; lysosome; pH

DOI: https://doi.org/10.1080/15548627.2023.2274253

Int J Mol Sci. 2023 Nov 06. pii: 16008. [Epub ahead of print]24(21):

CD38 Deficiency Alleviates Diabetic Cardiomyopathy by Coordinately Inhibiting Pyroptosis and Apoptosis.

Ling-Fang Wang, Qian Li, Ke Wen, Qi-Hang Zhao, Ya-Ting Zhang, Jia-Le Zhao, Qi Ding, Xiao-Hui Guan, Yun-Fei Xiao, Ke-Yu Deng, Hong-Bo Xin.

Diabetic cardiomyopathy is one of the diabetes mellitus-induced cardiovascular complications that can result in heart failure in severe cases, which is characterized by cardiomyocyte apoptosis, local inflammation, oxidative stress, and myocardial fibrosis. CD38, a main hydrolase of NAD+ in mammals, plays an important role in various cardiovascular diseases, according to our previous studies. However, the role of CD38 in diabetes-induced cardiomyopathy is still unknown. Here, we report that global deletion of the CD38 gene significantly prevented diabetic cardiomyopathy induced by high-fat diet plus streptozotocin (STZ) injection in CD38 knockout (CD38-KO) mice. We observed that CD38 expression was up-regulated, whereas the expression of Sirt3 was down-regulated in the hearts of diabetic mice. CD38 deficiency significantly promoted glucose metabolism and improved cardiac functions, exemplified by increased left ventricular ejection fraction and fractional shortening. In addition, we observed that CD38 deficiency markedly decreased diabetes or high glucose and palmitic acid (HG + PA)-induced pyroptosis and apoptosis in CD38 knockout hearts or cardiomyocytes, respectively. Furthermore, we found that the expression levels of Sirt3, mainly located in mitochondria, and its target gene FOXO3a were increased in CD38-deficient hearts and cardiomyocytes with CD38 knockdown under diabetic induction conditions. In conclusion, we demonstrated that CD38 deficiency protected mice from diabetes-induced diabetic cardiomyopathy by reducing pyroptosis and apoptosis via activating NAD+/Sirt3/FOXO3a signaling pathways.

Keywords: CD38; Sirt3; apoptosis; diabetic cardiomyopathy; pyroptosis

DOI: https://doi.org/10.3390/ijms242116008

Cell Mol Life Sci. 2023 Nov 11. 80(12): 358

TFEB SUMOylation in macrophages accelerates atherosclerosis by promoting the formation of foam cells through inhibiting lysosomal activity.

Kezhou Wang, Wei Zhou, Gaolei Hu, Lifeng Wang, Rong Cai, Tian Tian.

Atherosclerosis (AS) is a serious cardiovascular disease. One of its hallmarks is hyperlipidemia. Inhibiting the formation of macrophage foam cells is critical for alleviating AS. Transcription factor EB (TFEB) can limit the formation of macrophage foam cells by upregulating lysosomal activity. We examined whether TFEB SUMOylation is involved in this progress during AS. In this study, we investigated the role of TFEB SUMOylation in macrophages in AS using TFEB SUMOylation deficiency Ldlr-/- (TFEB-KR: Ldlr-/-) transgenic mice and TFEB-KR bone marrow-derived macrophages. We observed that TFEB-KR: Ldlr-/- atherosclerotic mice had thinner plaques and macrophages with higher lysosomal activity when compared to WT: Ldlr-/- mice. TFEB SUMOylation in macrophages decreased after oxidized low-density lipoprotein (OxLDL) treatment in vitro. Compared with wild type macrophages, TFEB-KR macrophages exhibited less lipid deposition after OxLDL treatment. Our study demonstrated that in AS, deSUMOylation of TFEB could inhibit the formation of macrophage foam cells through enhancing lysosomal biogenesis and autophagy, further reducing the accumulation of lipids in macrophages, and ultimately alleviating the development of AS. Thus, TFEB SUMOylation can be a switch to modulate macrophage foam cells formation and used as a potential target for AS therapy.

Keywords: Atherosclerosis; Macrophage foam cells; SUMOylation; TFEB

DOI: https://doi.org/10.1007/s00018-023-04981-8