bims-lymeca 2023-07-23 papers

Trends Cell Biol. 2023 Jul 18. pii: S0962-8924(23)00128-9. [Epub ahead of print]

Lysosomal enzyme trafficking: from molecular mechanisms to human diseases.

Thomas Braulke, Jan E Carette, Wilhelm Palm.

Lysosomes degrade and recycle macromolecules that are delivered through the biosynthetic, endocytic, and autophagic routes. Hydrolysis of the different classes of macromolecules is catalyzed by about 70 soluble enzymes that are transported from the Golgi apparatus to lysosomes in a mannose 6-phosphate (M6P)-dependent process. The molecular machinery that generates M6P tags for receptor-mediated targeting of lysosomal enzymes was thought to be understood in detail. However, recent studies on the M6P pathway have identified a previously uncharacterized core component, yielded structural insights in known components, and uncovered functions in various human diseases. Here we review molecular mechanisms of lysosomal enzyme trafficking and discuss its relevance for rare lysosomal disorders, cancer, and viral infection.

Keywords: LYSET; cancer metabolism; lysosomal enzymes; lysosomal storage disorders; mannose 6-phosphate pathway; viral infections

DOI: https://doi.org/10.1016/j.tcb.2023.06.005

Curr Opin Cell Biol. 2023 Jul 13. pii: S0955-0674(23)00056-X. [Epub ahead of print]83 102207

PI4KA and PIKfyve: Essential phosphoinositide signaling enzymes involved in myriad human diseases.

Isobel Barlow-Busch, Alexandria L Shaw, John E Burke.

Lipid phosphoinositides are master regulators of multiple cellular functions. Misregulation of the activity of the lipid kinases that generate phosphoinositides is causative of human diseases, including cancer, neurodegeneration, developmental disorders, immunodeficiencies, and inflammatory disease. This review will present a summary of recent discoveries on the roles of two phosphoinositide kinases (PI4KA and PIKfyve), which have emerged as targets for therapeutic intervention. Phosphatidylinositol 4-kinase alpha (PI4KA) generates PI4P at the plasma membrane and PIKfyve generates PI(3,5)P2 at endo-lysosomal membranes. Both of these enzymes exist as multi-protein mega complexes that are under myriad levels of regulation. Human disease can be caused by either loss or gain-of-function of these complexes, so understanding how they are regulated will be essential in the design of therapeutics. We will summarize insight into how these enzymes are regulated by their protein-binding partners, with a major focus on the unanswered questions of how their activity is controlled.

DOI: https://doi.org/10.1016/j.ceb.2023.102207

Biochim Biophys Acta Mol Cell Res. 2023 Jul 16. pii: S0167-4889(23)00109-X. [Epub ahead of print]1870(7): 119537

Therapeutic strategies targeting AMPK-dependent autophagy in cancer cells.

Wenbin Yuan, Wanyi Fang, Rui Zhang, Hao Lyu, Shuai Xiao, Dong Guo, Declan William Ali, Marek Michalak, Xing-Zhen Chen, Cefan Zhou, Jingfeng Tang.

Macroautophagy is a health-modifying process of engulfing misfolded or aggregated proteins or damaged organelles, coating these proteins or organelles into vesicles, fusion of vesicles with lysosomes to form autophagic lysosomes, and degradation of the encapsulated contents. It is also a self-rescue strategy in response to harsh environments and plays an essential role in cancer cells. AMP-activated protein kinase (AMPK) is the central pathway that regulates autophagy initiation and autophagosome formation by phosphorylating targets such as mTORC1 and unc-51 like activating kinase 1 (ULK1). AMPK is an evolutionarily conserved serine/threonine protein kinase that acts as an energy sensor in cells and regulates various metabolic processes, including those involved in cancer. The regulatory network of AMPK is complicated and can be regulated by multiple upstream factors, such as LKB1, AKT, PPAR, SIRT1, or noncoding RNAs. Currently, AMPK is being investigated as a novel target for anticancer therapies based on its role in macroautophagy regulation. Herein, we review the effects of AMPK-dependent autophagy on tumor cell survival and treatment strategies targeting AMPK.

Keywords: AMPK; Autophagy; Cancer therapy; Metabolism; Tumor

DOI: https://doi.org/10.1016/j.bbamcr.2023.119537

Front Mol Neurosci. 2023 ;16 1135015

Structural and functional understanding of disease-associated mutations in V-ATPase subunit a1 and other isoforms.

Karen Indrawinata, Peter Argiropoulos, Shuzo Sugita.

The vacuolar-type ATPase (V-ATPase) is a multisubunit protein composed of the cytosolic adenosine triphosphate (ATP) hydrolysis catalyzing V1 complex, and the integral membrane complex, Vo, responsible for proton translocation. The largest subunit of the Vo complex, subunit a, enables proton translocation upon ATP hydrolysis, mediated by the cytosolic V1 complex. Four known subunit a isoforms (a1-a4) are expressed in different cellular locations. Subunit a1 (also known as Voa1), the neural isoform, is strongly expressed in neurons and is encoded by the ATP6V0A1 gene. Global knockout of this gene in mice causes embryonic lethality, whereas pyramidal neuron-specific knockout resulted in neuronal cell death with impaired spatial and learning memory. Recently reported, de novo and biallelic mutations of the human ATP6V0A1 impair autophagic and lysosomal activities, contributing to neuronal cell death in developmental and epileptic encephalopathies (DEE) and early onset progressive myoclonus epilepsy (PME). The de novo heterozygous R740Q mutation is the most recurrent variant reported in cases of DEE. Homology studies suggest R740 deprotonates protons from specific glutamic acid residues in subunit c, highlighting its importance to the overall V-ATPase function. In this paper, we discuss the structure and mechanism of the V-ATPase, emphasizing how mutations in subunit a1 can lead to lysosomal and autophagic dysfunction in neurodevelopmental disorders, and how mutations to the non-neural isoforms, a2-a4, can also lead to various genetic diseases. Given the growing discovery of disease-causing variants of V-ATPase subunit a and its function as a pump-based regulator of intracellular organelle pH, this multiprotein complex warrants further investigation.

Keywords: R740; V-ATPase; developmental and epileptic encephalopahties; neurodevelopmental disorders; progressive myoclonus epilepsy; subunit a1

DOI: https://doi.org/10.3389/fnmol.2023.1135015

Cold Spring Harb Perspect Med. 2023 Jul 17. pii: a041383. [Epub ahead of print]

Monitoring the Cell Cycle of Tumor Cells in Mouse Models of Human Cancer.

Taylar Hammond, Julien Sage.

Cell division is obligatory to tumor growth. However, both cancer cells and noncancer cells in tumors can be found in distinct stages of the cell cycle, which may inform the growth potential of these tumors, their propensity to metastasize, and their response to therapy. Hence, it is of utmost importance to monitor the cell cycle of tumor cells. Here we discuss well-established methods and new genetic advances to track the cell cycle of tumor cells in mouse models of human cancer. We also review recent genetic studies investigating the role of the cell-cycle machinery in the growth of tumors in vivo, with a focus on the machinery regulating the G1/S transition of the cell cycle.

DOI: https://doi.org/10.1101/cshperspect.a041383

Elife. 2023 07 17. pii: e89825. [Epub ahead of print]12

How nearby nutrients shape tumor growth.

Nada Kalaany.

Studying the nutrient composition immediately surrounding pancreatic cancer cells provides new insights into their metabolic properties and how they can evade the immune system to promote disease progression.

Keywords: amino acid homeostasis; biochemistry; cancer; cancer biology; chemical biology; human; immunotherapy; metabolism; mouse; nutrient stress; tumor microenvironment

DOI: https://doi.org/10.7554/eLife.89825