bims-lypmec Biomed News
on Lysosomal positioning and metabolism in cardiomyocytes
Issue of 2024‒03‒31
seven papers selected by
Satoru Kobayashi, New York Institute of Technology
  1. The race to uncover fission factors for lysosomal organelles heats up.
  2. The HEAT repeat protein HPO-27 is a lysosome fission factor.
  3. Stress-induced microautophagy is coordinated with lysosome biogenesis and regulated by PIKfyve.
  4. SNX8 enables lysosome reformation and reverses lysosomal storage disorder.
  5. A novel pH-sensitive hemi-cyanine containing tetrahydropyridine ring near-infrared fluorescence probe with lysosome-targeting ability.
  6. Targeting of lysosomal-bound protein mEAK-7 for cancer therapy.
  7. Post-Translational Modifications and Diabetes.
  1. Nature. 2024 Mar 27.
    The race to uncover fission factors for lysosomal organelles heats up.
    Shilpa Gopan, Thomas J Pucadyil.
      
    Keywords:  Cell biology
    DOI:  https://doi.org/10.1038/d41586-024-00851-w
  2. Nature. 2024 Mar 27.
    The HEAT repeat protein HPO-27 is a lysosome fission factor.
    Letao Li, Xilu Liu, Shanshan Yang, Meijiao Li, Yanwei Wu, Siqi Hu, Wenjuan Wang, Amin Jiang, Qianqian Zhang, Junbing Zhang, Xiaoli Ma, Junyan Hu, Qiaohong Zhao, Yubing Liu, Dong Li, Junjie Hu, Chonglin Yang, Wei Feng, Xiaochen Wang.
      Lysosomes are degradation and signalling centres crucial for homeostasis, development and ageing1. To meet diverse cellular demands, lysosomes remodel their morphology and function through constant fusion and fission2,3. Little is known about the molecular basis of fission. Here we identify HPO-27, a conserved HEAT repeat protein, as a lysosome scission factor in Caenorhabditis elegans. Loss of HPO-27 impairs lysosome fission and leads to an excessive tubular network that ultimately collapses. HPO-27 and its human homologue MROH1 are recruited to lysosomes by RAB-7 and enriched at scission sites. Super-resolution imaging, negative-staining electron microscopy and in vitro reconstitution assays reveal that HPO-27 and MROH1 self-assemble to mediate the constriction and scission of lysosomal tubules in worms and mammalian cells, respectively, and assemble to sever supported membrane tubes in vitro. Loss of HPO-27 affects lysosomal morphology, integrity and degradation activity, which impairs animal development and longevity. Thus, HPO-27 and MROH1 act as self-assembling scission factors to maintain lysosomal homeostasis and function.
    DOI:  https://doi.org/10.1038/s41586-024-07249-8
  3. Mol Biol Cell. 2024 Mar 27. mbcE23080332
    Stress-induced microautophagy is coordinated with lysosome biogenesis and regulated by PIKfyve.
    Alison D Klein, Kayla L Petruzzi, Chan Lee, Michael Overholtzer.
      Lysosome turnover and biogenesis are induced in response to treatment of cells with agents that cause membrane rupture, but whether other stress conditions engage similar homeostatic mechanisms is not well understood. Recently we described a form of selective turnover of lysosomes that is induced by metabolic stress or by treatment of cells with ionophores or lysosomotropic agents, involving the formation of intraluminal vesicles within intact organelles through microautophagy. Selective turnover involves non-canonical autophagy and the lipidation of LC3 onto lysosomal membranes, as well as the autophagy gene-dependent formation of intraluminal vesicles. Here we find a form of microautophagy induction that requires activity of the lipid kinase PIKfyve and is associated with the nuclear translocation of TFEB, a known mediator of lysosome biogenesis. We show that LC3 undergoes turnover during this process, and that PIKfyve is required for the formation of intraluminal vesicles and LC3 turnover, but not for LC3 lipidation onto lysosomal membranes, demonstrating that microautophagy is regulated by PIKfyve downstream of non-canonical autophagy. We further show that TFEB activation requires non-canonical autophagy but not PIKfyve, distinguishing the regulation of biogenesis from microautophagy occurring in response to agents that induce lysosomal stress. [Media: see text] [Media: see text] [Media: see text] [Media: see text] [Media: see text].
    DOI:  https://doi.org/10.1091/mbc.E23-08-0332
  4. Nat Commun. 2024 Mar 22. 15(1): 2553
    SNX8 enables lysosome reformation and reverses lysosomal storage disorder.
    Xinran Li, Cong Xiang, Shilei Zhu, Jiansheng Guo, Chang Liu, Ailian Wang, Jin Cao, Yan Lu, Dante Neculai, Pinglong Xu, Xin-Hua Feng.
      Lysosomal Storage Disorders (LSDs), which share common phenotypes, including enlarged lysosomes and defective lysosomal storage, are caused by mutations in lysosome-related genes. Although gene therapies and enzyme replacement therapies have been explored, there are currently no effective routine therapies against LSDs. During lysosome reformation, which occurs when the functional lysosome pool is reduced, lysosomal lipids and proteins are recycled to restore lysosome functions. Here we report that the sorting nexin protein SNX8 promotes lysosome tubulation, a process that is required for lysosome reformation, and that loss of SNX8 leads to phenotypes characteristic of LSDs in human cells. SNX8 overexpression rescued features of LSDs in cells, and AAV-based delivery of SNX8 to the brain rescued LSD phenotypes in mice. Importantly, by screening a natural compound library, we identified three small molecules that enhanced SNX8-lysosome binding and reversed LSD phenotypes in human cells and in mice. Altogether, our results provide a potential solution for the treatment of LSDs.
    DOI:  https://doi.org/10.1038/s41467-024-46705-x
  5. Spectrochim Acta A Mol Biomol Spectrosc. 2024 Mar 20. pii: S1386-1425(24)00328-7. [Epub ahead of print]314 124162
    A novel pH-sensitive hemi-cyanine containing tetrahydropyridine ring near-infrared fluorescence probe with lysosome-targeting ability.
    Hongwei Zhao, Jingrong Guo, Jiameng Huai, Ruyue Li, Hui Han, Xiao Huang, Yuna Jiang, Shaomin Shuang.
      In recent years, hemi-cyanine dyes have been widely used as biological probes due to their red-light emission characteristics and high fluorescence quantum yield. In this study, we synthesized a novel hemi-cyanine dye containing a tetrahydropyridine ring. A lysosomal target was introduced into its structure to create a new pH-sensitive near-infrared fluorescent probe that successfully targeted lysosomes. The results showed that when the probe solution was excited at the absorption wavelength of 650 nm, its fluorescence emission wavelength was about 700 nm, and the peak intensity changed with different pH values in a wide range. Therefore, this probe enabled non-invasive detection of changes in the acidic environment of lysosomes in living organisms and showed good imaging capabilities. Moreover, the probe displays high sensitivity and good stability. The theoretical calculation of a probe structure has also been completed to discuss the relationship between structure and property.
    DOI:  https://doi.org/10.1016/j.saa.2024.124162
  6. Front Oncol. 2024 ;14 1375498
    Targeting of lysosomal-bound protein mEAK-7 for cancer therapy.
    Insoon Chang, Yi-Ling Loo, Jay Patel, Joe Truong Nguyen, Jin Koo Kim, Paul H Krebsbach.
      mEAK-7 (mammalian EAK-7 or MTOR-associated protein, eak-7 homolog), is an evolutionarily conserved lysosomal membrane protein that is highly expressed in several cancer cells. Multiple recent studies have identified mEAK-7 as a positive activator of mTOR (mammalian/mechanistic target of rapamycin) signaling via an alternative mTOR complex, implying that mEAK-7 plays an important role in the promotion of cancer proliferation and migration. In addition, structural analyses investigating interactions between mEAK-7 and V-ATPase, a protein complex responsible for regulating pH homeostasis in cellular compartments, have suggested that mEAK-7 may contribute to V-ATPase-mediated mTORC1 activation. The C-terminal α-helix of mEAK-7 binds to the D and B subunits of the V-ATPase, creating a pincer-like grip around its B subunit. This binding undergoes partial disruption during ATP hydrolysis, potentially enabling other proteins such as mTOR to bind to the α-helix of mEAK-7. mEAK-7 also promotes chemoresistance and radiation resistance by sustaining DNA damage-mediated mTOR signaling through interactions with DNA-PKcs (DNA-dependent protein kinase catalytic subunit). Taken together, these findings indicate that mEAK-7 may be a promising therapeutic target against tumors. However, the precise molecular mechanisms and signal transduction pathways of mEAK-7 in cancer remain largely unknown, motivating the need for further investigation. Here, we summarize the current known roles of mEAK-7 in normal physiology and cancer development by reviewing the latest studies and discuss potential future developments of mEAK-7 in targeted cancer therapy.
    Keywords:  V-ATPase; cancer; lysosomal membrane protein; mEAK-7; mTOR signaling
    DOI:  https://doi.org/10.3389/fonc.2024.1375498
  7. Biomolecules. 2024 Mar 06. pii: 310. [Epub ahead of print]14(3):
    Post-Translational Modifications and Diabetes.
    Chiranjeev Sharma, Abu Hamza, Emily Boyle, Dickson Donu, Yana Cen.
      Diabetes and its associated complications have increasingly become major challenges for global healthcare. The current therapeutic strategies involve insulin replacement therapy for type 1 diabetes (T1D) and small-molecule drugs for type 2 diabetes (T2D). Despite these advances, the complex nature of diabetes necessitates innovative clinical interventions for effective treatment and complication prevention. Accumulative evidence suggests that protein post-translational modifications (PTMs), including glycosylation, phosphorylation, acetylation, and SUMOylation, play important roles in diabetes and its pathological consequences. Therefore, the investigation of these PTMs not only sheds important light on the mechanistic regulation of diabetes but also opens new avenues for targeted therapies. Here, we offer a comprehensive overview of the role of several PTMs in diabetes, focusing on the most recent advances in understanding their functions and regulatory mechanisms. Additionally, we summarize the pharmacological interventions targeting PTMs that have advanced into clinical trials for the treatment of diabetes. Current challenges and future perspectives are also provided.
    Keywords:  T1D; T2D; clinical trials; diabetes; post-translational modifications
    DOI:  https://doi.org/10.3390/biom14030310
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