bims-lypmec 2024-12-01 papers

EMBO J. 2024 Nov 25.

GOLPH3 and GOLPH3L maintain Golgi localization of LYSET and a functional mannose 6-phosphate transport pathway.

Berit K Brauer, Zilei Chen, Felix Beirow, Jiaran Li, Daniel Meisinger, Emanuela Capriotti, Michaela Schweizer, Lea Wagner, Jascha Wienberg, Laura Hobohm, Lukas Blume, Wenjie Qiao, Yoshiki Narimatsu, Jan E Carette, Henrik Clausen, Dominic Winter, Thomas Braulke, Sabrina Jabs, Matthias Voss.

Glycosylation, which plays an important role in modifying lipids and sorting of proteins, is regulated by asymmetric intra-Golgi distribution and SPPL3-mediated cleavage of Golgi enzymes. We found that cells lacking LYSET/TMEM251, a retention factor for Golgi N-acetylglucosamine-1-phosphotransferase (GNPT), display SPPL3-dependent hypersecretion of the Golgi membrane protein B4GALT5. We demonstrate that in wild-type cells B4GALT5 is tagged with mannose 6-phosphate (M6P), a sorting tag typical of soluble lysosomal hydrolases. Hence, M6P-tagging of B4GALT5 may represent a novel degradative lysosomal pathway. We also observed B4GALT5 hypersecretion and prominent destabilization of LYSET-GNPT complexes, impaired M6P-tagging, and disturbed maturation and trafficking of lysosomal enzymes in multiple human cell lines lacking the COPI adaptors GOLPH3 and GOLPH3L. Mechanistically, we identified LYSET as a novel, atypical client of GOLPH3/GOLPH3L. Thus, by ensuring the cis-Golgi localization of the LYSET-GNPT complex and maintaining its Golgi polarity, GOLPH3/GOLPH3L is essential for the integrity of the M6P-tagging machinery and homeostasis of lysosomes.

Keywords: Glycosyltransferase Secretion; Golgi Apparatus; Intramembrane Proteolysis; Lysosomes; Mannose 6-Phophate Tagging

DOI: https://doi.org/10.1038/s44318-024-00305-z

Biochem Soc Trans. 2024 Nov 27. pii: BST20240262. [Epub ahead of print]

The role of protein O-GlcNAcylation in diabetic cardiomyopathy.

John C Chatham, Adam R Wende.

It is well established that diabetes markedly increases the risk of multiple types of heart disease including heart failure. However, despite substantial improvements in the treatment of heart failure in recent decades the relative increased risk associated with diabetes remains unchanged. There is increasing appreciation of the importance of the post translational modification by O-linked-N-acetylglucosamine (O-GlcNAc) of serine and threonine residues on proteins in regulating cardiomyocyte function and mediating stress responses. In response to diabetes there is a sustained increase in cardiac O-GlcNAc levels, which has been attributed to many of the adverse effects of diabetes on the heart. Here we provide an overview of potential mechanisms by which increased cardiac O-GlcNAcylation contributes to the adverse effects on the heart and highlight some of the key gaps in our knowledge.

Keywords: O-GlcNAc; diabetes; glycosylation; myocardium

DOI: https://doi.org/10.1042/BST20240262

Sci Rep. 2024 Nov 29. 14(1): 29651

Endogenous chondroitin extends lifespan by inhibiting VHA-7-mediated tubular lysosome formation.

Yukimasa Shibata, Yuri Tanaka, Shunsuke Mori, Kaito Mitsuzumi, Shion Fujii, Hiroyuki Sasakura, Yuki Morioka, Kenji Sugioka, Kosei Takeuchi, Kiyoji Nishiwaki.

Chondroitin extends lifespan and healthspan in C. elegans, but the relationship between extracellular chondroitin and intracellular anti-aging mechanisms is unknown. The basement membrane (BM) that contains chondroitin proteoglycans is anchored to cells via hemidesmosomes (HDs), and it accumulates damage with aging. In this study, we found that chondroitin regulates aging through the formation of HDs and inhibition of tubular lysosomes (TLs). Reduction of chondroitin due to a mutation in sqv-5/Chondroitin synthase (ChSy) causes the earlier and excessive formation of TLs and leakage of the lysosomal nuclease in a manner dependent on VHA-7, the a-subunit of V-type ATPase. VHA-7, whose mutation suppresses the short lifespan of the sqv-5 mutant, is initially localized to the basal side of the hypodermal cells and transported to lysosomes with aging. These results demonstrate that endogenous chondroitin suppresses aging by inhibiting the earlier excessive formation of TLs. This is a novel anti-aging mechanism that is controlled by the BM.

Keywords: Aging; Basement membrane; Chondroitin; Hemidesmosomes; Tubular lysosomes

DOI: https://doi.org/10.1038/s41598-024-80242-3

Int J Mol Sci. 2024 Nov 12. pii: 12117. [Epub ahead of print]25(22):

Nuclear mTORC1 Live-Cell Sensor nTORSEL Reports Differential Nuclear mTORC1 Activity in Cell Lines.

Yifan Wang, Canrong Li, Yingyi Ouyang, Xiaoduo Xie.

The mammalian or mechanistic target of rapamycin complex 1 (mTORC1) is activated on the surface of lysosomes and phosphorylates substrates at various subcellular locations, including the lysosome, cytosol, and nucleus. However, the signaling and biological functions of nuclear mTORC1 (nmTORC1) are not well understood, primarily due to limited tools for monitoring mTORC1 activity in the nucleus. In this study, we developed a genetically encoded nmTORC1 sensor, termed nTORSEL, based on the phosphorylation of the eukaryotic initiation factor 4E (eIF4E) binding protein 1 (4EBP1) by mTORC1 within the nucleus. nTORSEL, like its predecessor TORSEL, exhibits a fluorescent punctate pattern in the nucleus through multivalent protein-protein interactions between oligomerized 4EBP1 and eIF4E when nmTORC1 activity is low. We validated nTORSEL using biochemical analyses and imaging techniques across representative cell lines with varying levels of nmTORC1 activity. Notably, nTORSEL specifically detects physiological, pharmacological, and genetic inhibition of nmTORC1 in mouse embryonic fibroblast (MEF) cells but not in HEK293T cells. Therefore, nTORSEL is an effective tool for investigating nuclear mTORC1 signaling in cell lines.

Keywords: PI3K-AKT-mTOR pathway; amino acid; fluorescent reporter; live-cell sensor; nuclear mTORC1

DOI: https://doi.org/10.3390/ijms252212117

Heliyon. 2024 Nov 15. 10(21): e39996

Mechanistic insights and therapeutic potential of astilbin and apigenin in diabetic cardiomyopathy.

Sachin Dhiman, Sanchit Dhankhar, Anjali Garg, Manni Rohilla, Monika Saini, Thakur Gurjeet Singh, Samrat Chauhan, Samy Selim, Soad K Al Jaouni, Sabina Yasmin, Naseem Begum, Aziza Alshahrani, Mohammad Yousuf Ansari.

Diabetic cardiomyopathy (DCM) represents a critical complication of Diabetes mellitus (DM), characterized by structural and functional changes in the myocardium independent of coronary artery disease or hypertension. Emerging evidence highlights the significant roles of phytochemicals, particularly astilbin and apigenin, in modulating key molecular pathways implicated in DCM. This review synthesizes current mechanistic insights and therapeutic potential of these compounds, focusing on their interactions with AMP-activated protein kinase (AMPK), peroxisome proliferator-activated receptors (PPARs), O-linked N-acetylglucosamine (O-GlcNAc), sodium-glucose co-transporter 2 (SGLT2), protein kinase C (PKC), nuclear factor kappa B (NF-κB), mitogen-activated protein kinase (MAPK), and c-Jun N-terminal kinase (JNK) pathways. Astilbin and apigenin have demonstrated the ability to improve cardiac function, mitigate oxidative stress, and reduce inflammatory responses in diabetic conditions. By activating AMPK and PPARs, these flavonoids enhance glucose uptake and fatty acid oxidation, contributing to improved metabolic homeostasis. Their inhibition of O-GlcNAcylation, SGLT2 activity, and PKC signaling further attenuates hyperglycemia-induced cellular damage. Additionally, suppression of NF-κB, MAPK, and JNK pathways by astilbin and apigenin results in reduced pro-inflammatory cytokine production and apoptotic cell death. Collectively, these interactions position astilbin and apigenin as promising therapeutic agents for ameliorating DCM, offering novel avenues for treatment strategies aimed at modulating multiple pathogenic pathways.

Keywords: Apigenin; Astilbin; Cardiomyopathy; Diabetes

DOI: https://doi.org/10.1016/j.heliyon.2024.e39996

Front Endocrinol (Lausanne). 2024 ;15 1421838

Ferroptosis in diabetic cardiomyopathy: from its mechanisms to therapeutic strategies.

Meimei Tian, Xinli Huang, Min Li, Pingping Lou, Huijie Ma, Xinli Jiang, Yaru Zhou, Yan Liu.

Diabetic cardiomyopathy (DCM) is defined as structural and functional cardiac abnormalities in diabetes, and cardiomyocyte death is the terminal event of DCM. Ferroptosis is iron-dependent oxidative cell death. Evidence has indicated that iron overload and ferroptosis play important roles in the pathogenesis of DCM. Mitochondria, an important organelle in iron homeostasis and ROS production, play a crucial role in cardiomyocyte ferroptosis in diabetes. Studies have shown some anti-diabetic medicines, plant extracts, and ferroptosis inhibitors might improve DCM by alleviating ferroptosis. In this review, we systematically reviewed the evidence of ferroptosis in DCM. Anti-ferroptosis might be a promising therapeutic strategy for the treatment of DCM.

Keywords: diabetic cardiomyopathy; ferroptosis; iron metabolism; mitochondria; therapy

DOI: https://doi.org/10.3389/fendo.2024.1421838