bims-lycede 2024-11-24 papers

NAR Cancer. 2024 Dec;6(4): zcae043

Integration of transcriptional and epigenetic regulation of TFEB reveals its dual functional roles in Pan-cancer.

Jing-Fang Luo, Shijia Wang, Jiajing Fu, Peng Xu, Ningyi Shao, Jia-Hong Lu, Chen Ming.

Transcription factor EB (TFEB) mainly regulates the autophagy-lysosomal pathway, associated with many diseases, including cancer. However, the role of TFEB in pan-cancer has not been investigated systematically. In this study, we comprehensively analyzed TFEB targets under three stresses in Hela cells by cross-validation of RNA-seq and ChIP-seq. 1712 novel TFEB targets have not been reported in the Gene Set Enrichment Analysis and ChIP Enrichment Analysis databases. We further investigated their distributions and roles among the pan-cancer co-expression networks across 32 cancers constructed by multiscale embedded gene co-expression network analysis (MEGENA) based on the Cancer Genome Atlas (TCGA) cohort. Specifically, TFEB might serve as a hidden player with multifaceted functions in regulating pan-cancer risk factors, e.g. CXCL2, PKMYT1 and BUB1, associated with cell cycle and immunosuppression. TFEB might also regulate protective factors, e.g. CD79A, related to immune promotion in the tumor microenvironment. We further developed a Shiny app website to present the comprehensive regulatory targets of TFEB under various stimuli, intending to support further research on TFEB functions. Summarily, we provided references for the TFEB downstream targets responding to three stresses and the dual roles of TFEB and its targets in pan-cancer, which are promising anticancer targets that warrant further exploration.

DOI: https://doi.org/10.1093/narcan/zcae043

Signal Transduct Target Ther. 2024 Nov 18. 9(1): 305

Membraneless organelles in health and disease: exploring the molecular basis, physiological roles and pathological implications.

Yangxin Li, Yuzhe Liu, Xi-Yong Yu, Yan Xu, Xiangbin Pan, Yi Sun, Yanli Wang, Yao-Hua Song, Zhenya Shen.

Once considered unconventional cellular structures, membraneless organelles (MLOs), cellular substructures involved in biological processes or pathways under physiological conditions, have emerged as central players in cellular dynamics and function. MLOs can be formed through liquid-liquid phase separation (LLPS), resulting in the creation of condensates. From neurodegenerative disorders, cardiovascular diseases, aging, and metabolism to cancer, the influence of MLOs on human health and disease extends widely. This review discusses the underlying mechanisms of LLPS, the biophysical properties that drive MLO formation, and their implications for cellular function. We highlight recent advances in understanding how the physicochemical environment, molecular interactions, and post-translational modifications regulate LLPS and MLO dynamics. This review offers an overview of the discovery and current understanding of MLOs and biomolecular condensate in physiological conditions and diseases. This article aims to deliver the latest insights on MLOs and LLPS by analyzing current research, highlighting their critical role in cellular organization. The discussion also covers the role of membrane-associated condensates in cell signaling, including those involving T-cell receptors, stress granules linked to lysosomes, and biomolecular condensates within the Golgi apparatus. Additionally, the potential of targeting LLPS in clinical settings is explored, highlighting promising avenues for future research and therapeutic interventions.

DOI: https://doi.org/10.1038/s41392-024-02013-w

Sci Adv. 2024 Nov 22. 10(47): eadr5807

Structure of the human TSC:WIPI3 lysosomal recruitment complex.

Charles Bayly-Jones, Christopher J Lupton, Laura D'Andrea, Yong-Gang Chang, Gareth D Jones, Joel R Steele, Hari Venugopal, Ralf B Schittenhelm, Michelle L Halls, Andrew M Ellisdon.

Tuberous sclerosis complex (TSC) is targeted to the lysosomal membrane, where it hydrolyzes RAS homolog-mTORC1 binding (RHEB) from its GTP-bound to GDP-bound state, inhibiting mechanistic target of rapamycin complex 1 (mTORC1). Loss-of-function mutations in TSC cause TSC disease, marked by excessive tumor growth. Here, we overcome a high degree of continuous conformational heterogeneity to determine the 2.8-Å cryo-electron microscopy (cryo-EM) structure of the complete human TSC in complex with the lysosomal recruitment factor WD repeat domain phosphoinositide-interacting protein 3 (WIPI3). We discover a previously undetected amino-terminal TSC1 HEAT repeat dimer that clamps onto a single TSC wing and forms a phosphatidylinositol phosphate (PIP)-binding pocket, which specifically binds monophosphorylated PIPs. These structural advances provide a model by which WIPI3 and PIP-signaling networks coordinate to recruit TSC to the lysosomal membrane to inhibit mTORC1. The high-resolution TSC structure reveals previously unrecognized mutational hotspots and uncovers crucial insights into the mechanisms of TSC dysregulation in disease.

DOI: https://doi.org/10.1126/sciadv.adr5807

Trends Biochem Sci. 2024 Nov 15. pii: S0968-0004(24)00252-4. [Epub ahead of print]

TEX264-mediated selective autophagy directs DNA damage repair.

Yuxia Qi, Sho W Suzuki.

DNA is constantly subject to damage from endogenous and exogenous factors, leading to mutations and disease. While DNA is traditionally repaired in the nucleus, Lascaux et al. reveal a novel role for the lysosome in DNA repair, demonstrating that topoisomerase 1 (TOP1) cleavage complex (TOP1cc) DNA lesions are degraded via TEX264-mediated selective autophagy.

Keywords: DNA repair; TEX264; colorectal cancer; genome stability; selective autophagy; topoisomerase 1 cleavage complex

DOI: https://doi.org/10.1016/j.tibs.2024.10.012