bims-raghud Biomed News
on RagGTPases in human diseases
Issue of 2024–10–20
seven papers selected by
Irene Sambri, TIGEM
  1. Multiomics profiling of mouse polycystic kidney disease progression at a single-cell resolution.
  2. Transcription factor EB, a promising therapeutic target in cardiovascular disease.
  3. A TBK1-independent primordial function of STING in lysosomal biogenesis.
  4. USP7 protects TFEB from proteasome-mediated degradation.
  5. The role of SIRT1 in autophagy and drug resistance: unveiling new targets and potential biomarkers in cancer therapy.
  6. Mitophagy as a guardian against cellular aging.
  7. Autophagy and cancer therapy.
  1. Proc Natl Acad Sci U S A. 2024 Oct 22. 121(43): e2410830121
    Multiomics profiling of mouse polycystic kidney disease progression at a single-cell resolution.
    Yoshiharu Muto, Yasuhiro Yoshimura, Haojia Wu, Monica Chang-Panesso, Nicolas Ledru, Owen M Woodward, Patricia Outeda, Tao Cheng, Moe R Mahjoub, Terry J Watnick, Benjamin D Humphreys.
      Autosomal dominant polycystic kidney disease (ADPKD) is the most common hereditary kidney disease and causes significant morbidity, ultimately leading to kidney failure. PKD pathogenesis is characterized by complex and dynamic alterations in multiple cell types during disease progression, hampering a deeper understanding of disease mechanism and the development of therapeutic approaches. Here, we generate a single-nucleus multimodal atlas of an orthologous mouse PKD model at early, mid, and late timepoints, consisting of 125,434 single-nucleus transcriptomic and epigenetic multiomes. We catalog differentially expressed genes and activated epigenetic regions in each cell type during PKD progression, characterizing cell-type-specific responses to Pkd1 deletion. We describe heterogeneous, atypical collecting duct cells as well as proximal tubular cells that constitute cyst epithelia in PKD. The transcriptional regulation of the cyst lining cell marker GPRC5A is conserved between mouse and human PKD cystic epithelia, suggesting shared gene regulatory pathways. Our single-nucleus multiomic analysis of mouse PKD provides a foundation to understand the earliest changes molecular deregulation in a mouse model of PKD at a single-cell resolution.
    Keywords:  PKD1; mouse model; multiomics; polycystic kidney disease; single cell analysis
    DOI:  https://doi.org/10.1073/pnas.2410830121
  2. PeerJ. 2024 ;12 e18209
    Transcription factor EB, a promising therapeutic target in cardiovascular disease.
    Xin Yan, Li Yang, Xiaolei Fu, Xin Luo, Chengming Wang, Qiu Ping Xie, Fan OuYang.
      Cardiovascular disease (CVD) remains the major cause of morbidity and mortality around the world. Transcription factor EB (TFEB) is a master regulator of lysosome biogenesis and autophagy. Emerging studies revealed that TFEB also mediates cellular adaptation responses to various stimuli, such as mitochondrial dysfunction, pathogen infection and metabolic toxin. Based on its significant capability to modulate the autophagy-lysosome process (ALP), TFEB plays a critical role in the development of CVD. In this review, we briefly summarize that TFEB regulates cardiac dysfunction mainly through ameliorating lysosomal and mitochondrial dysfunction and reducing inflammation.
    Keywords:  Autophagic flux; Cardiovascular disease; Lysosome; TFEB
    DOI:  https://doi.org/10.7717/peerj.18209
  3. Mol Cell. 2024 Oct 17. pii: S1097-2765(24)00703-2. [Epub ahead of print]84(20): 3979-3996.e9
    A TBK1-independent primordial function of STING in lysosomal biogenesis.
    Bo Lv, William A Dion, Haoxiang Yang, Jinrui Xun, Do-Hyung Kim, Bokai Zhu, Jay Xiaojun Tan.
      Stimulator of interferon genes (STING) is activated in many pathophysiological conditions, leading to TBK1-dependent interferon production in higher organisms. However, primordial functions of STING independent of TBK1 are poorly understood. Here, through proteomics and bioinformatics approaches, we identify lysosomal biogenesis as an unexpected function of STING. Transcription factor EB (TFEB), an evolutionarily conserved regulator of lysosomal biogenesis and host defense, is activated by STING from multiple species, including humans, mice, and frogs. STING-mediated TFEB activation is independent of TBK1, but it requires STING trafficking and its conserved proton channel. GABARAP lipidation, stimulated by the channel of STING, is key for STING-dependent TFEB activation. STING stimulates global upregulation of TFEB-target genes, mediating lysosomal biogenesis and autophagy. TFEB supports cell survival during chronic sterile STING activation, a common condition in aging and age-related diseases. These results reveal a primordial function of STING in the biogenesis of lysosomes, essential organelles in immunity and cellular stress resistance.
    Keywords:  STING; STING channel; TBK1; TFE3; TFEB; autophagy; cGAS; chronic STING signaling; lysosome
    DOI:  https://doi.org/10.1016/j.molcel.2024.08.026
  4. Cell Rep. 2024 Oct 15. pii: S2211-1247(24)01223-3. [Epub ahead of print]43(11): 114872
    USP7 protects TFEB from proteasome-mediated degradation.
    Swati Keshri, Mariella Vicinanza, Michael Takla, David C Rubinsztein.
      The transcription factor EB (TFEB) is a master regulator of lysosomal biogenesis and autophagy. We identify a distinct nuclear interactome of TFEB, with ubiquitin-specific protease 7 (USP7) emerging as a key post-translational modulator of TFEB. Genetic depletion and inhibition of USP7 reveal its critical role in preserving TFEB stability within both nuclear and cytoplasmic compartments. Specifically, USP7 is identified as the deubiquitinase responsible for removing the K48-linked polyubiquitination signal from TFEB at lysine residues K116, K264, and K274, thereby preventing its proteasomal degradation. Functional assays demonstrate the involvement of USP7 in preserving TFEB-mediated transcriptional responses to nutrient deprivation while also modulating autophagy flux and lysosome biogenesis. As USP7 is a deubiquitinase that protects TFEB from proteasomal degradation, these findings provide the foundation for therapeutic targeting of the USP7-TFEB axis in conditions characterized by TFEB dysregulation and metabolic abnormalities, particularly in certain cancers.
    Keywords:  CP: Cell biology; CP: Molecular biology; TFEB; USP7; autophagy; lysosomal biogenesis; post-translational modifications; proteasomal degradation; ubiquitination
    DOI:  https://doi.org/10.1016/j.celrep.2024.114872
  5. Front Pharmacol. 2024 ;15 1469830
    The role of SIRT1 in autophagy and drug resistance: unveiling new targets and potential biomarkers in cancer therapy.
    Yujing Tang, Wantao Ju, Yanjun Liu, Qin Deng.
      Cancer, the world's second leading cause of death after cardiovascular diseases, is characterized by hallmarks such as uncontrolled cell growth, metastasis, angiogenesis, hypoxia, and resistance to therapy. Autophagy, a cellular process that can both support and inhibit cancer progression, plays a critical role in cancer development and progression. This process involves the formation of autophagosomes that ultimately fuse with lysosomes to degrade cellular components. A key regulator of this process is Sirtuin 1 (SIRT1), which significantly influences autophagy. This review delves into the role of SIRT1 in modulating autophagy and its broader impacts on carcinogenesis. SIRT1 regulates crucial autophagy mediators, such as AMP-activated protein kinase (AMPK) and mammalian target of rapamycin (mTOR), effectively promoting or suppressing autophagy. Beyond its direct effects on autophagy, SIRT1's regulatory actions extend to other cell death processes, including apoptosis and ferroptosis, thereby influencing tumor cell proliferation, metastasis, and chemotherapy responses. These insights underscore the complex interplay between SIRT1 and autophagy, with significant implications for cancer therapy. Targeting SIRT1 and its associated pathways presents a promising strategy to manipulate autophagy in cancer treatment. This review underscores the potential of SIRT1 as a therapeutic target, opening new avenues for enhancing cancer treatment efficacy.
    Keywords:  SIRT1; apoptosis; autophagy; drug resistance; ferroptosis; sirtuin family
    DOI:  https://doi.org/10.3389/fphar.2024.1469830
  6. Autophagy. 2024 Oct 14. 1-3
    Mitophagy as a guardian against cellular aging.
    Tetsushi Kataura, Niall Wilson, Gailing Ma, Viktor I Korolchuk.
      Mitophagy, the selective autophagic clearance of damaged mitochondria, is considered vital for maintaining mitochondrial quality and cellular homeostasis; however, its molecular mechanisms, particularly under basal conditions, and its role in cellular physiology remain poorly characterized. We recently demonstrated that basal mitophagy is a key feature of primary human cells and is downregulated by immortalization, suggesting its dependence on the primary cell state. Mechanistically, we demonstrated that the PINK1-PRKN-SQSTM1 pathway regulates basal mitophagy, with SQSTM1 sensing superoxide-enriched mitochondria through its redox-sensitive cysteine residues, which mediate SQSTM1 oligomerization and mitophagy activation. We developed STOCK1N-57534, a small molecule that targets and promotes this SQSTM1 activation mechanism. Treatment with STOCK1N-57534 reactivates mitophagy downregulated in senescent and naturally aged donor-derived primary cells, improving cellular senescence(-like) phenotypes. Our findings highlight that basal mitophagy is protective against cellular senescence and aging, positioning its pharmacological reactivation as a promising anti-aging strategy.Abbreviation: IR: ionizing radiation; ROS: reactive oxygen species; SARs: selective autophagy receptors.
    Keywords:  Aging; SQSTM1/p62; autophagy; mitochondria; mitophagy; senescence
    DOI:  https://doi.org/10.1080/15548627.2024.2414461
  7. Cancer Lett. 2024 Oct 10. pii: S0304-3835(24)00680-3. [Epub ahead of print] 217285
    Autophagy and cancer therapy.
    Julio M Pimentel, Jun Ying Zhou, Gen Sheng Wu.
      Autophagy is an intracellular degradation process that sequesters cytoplasmic components in double-membrane vesicles known as autophagosomes, which are degraded upon fusion with lysosomes. This pathway maintains the integrity of proteins and organelles while providing energy and nutrients to cells, particularly under nutrient deprivation. Deregulation of autophagy can cause genomic instability, low protein quality, and DNA damage, all of which can contribute to cancer. Autophagy can also be overactivated in cancer cells to aid in cancer cell survival and drug resistance. Emerging evidence indicates that autophagy has functions beyond cargo degradation, including roles in tumor immunity and cancer stem cell survival. Additionally, autophagy can also influence the tumor microenvironment. This feature warrants further investigation of the role of autophagy in cancer, in which autophagy manipulation can improve cancer therapies, including cancer immunotherapy. This review discusses recent findings on the regulation of autophagy and its role in cancer therapy and drug resistance.
    Keywords:  autophagy; cancer; resistance; therapy
    DOI:  https://doi.org/10.1016/j.canlet.2024.217285
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