bims-lypmec Biomed News
on Lysosomal positioning and metabolism in cardiomyocytes
Issue of 2023‒10‒29
eight papers selected by
Satoru Kobayashi, New York Institute of Technology
  1. ATG12-ATG5-TECPR1: an alternative E3-like complex utilized during the cellular response to lysosomal membrane damage.
  2. Rab12 is a regulator of LRRK2 and its activation by damaged lysosomes.
  3. Inducin Triggers LC3-Lipidation and ESCRT-Mediated Lysosomal Membrane Repair.
  4. Nutrient-regulated control of lysosome function by signaling lipid conversion.
  5. Spatacsin regulates directionality of lysosome trafficking by promoting the degradation of its partner AP5Z1.
  6. Lysosomal proteomics reveals mechanisms of neuronal apoE4-associated lysosomal dysfunction.
  7. mTORC1 and SGLT2 Inhibitors-A Therapeutic Perspective for Diabetic Cardiomyopathy.
  8. Distinguishing Lysosomal Acid Lipase Deficiency From Familial Hypercholesterolemia.
  1. Autophagy. 2023 Oct 23. 1-2
    ATG12-ATG5-TECPR1: an alternative E3-like complex utilized during the cellular response to lysosomal membrane damage.
    Dale P Corkery, Yao-Wen Wu.
      ATG16L1 is an essential component of the Atg8-family protein conjugation machinery, providing membrane targeting for the ATG12-ATG5 conjugate. Recently, we identified an alternative E3-like complex that functions independently of ATG16L1. This complex utilizes the autophagosome-lysosome tethering factor TECPR1 for membrane targeting. TECPR1 is recruited to damaged lysosomal membranes via a direct interaction with sphingomyelin. At the damaged membrane, TECPR1 assembles into an E3-like complex with ATG12-ATG5 to regulate unconventional LC3 lipidation and promote efficient lysosomal repair.
    Keywords:  ESCRT; TECPR1; lysophagy; lysosome; membrane repair
    DOI:  https://doi.org/10.1080/15548627.2023.2267414
  2. Elife. 2023 Oct 24. pii: e87255. [Epub ahead of print]12
    Rab12 is a regulator of LRRK2 and its activation by damaged lysosomes.
    Xiang Wang, Vitaliy V Bondar, Oliver B Davis, Michael T Maloney, Maayan Agam, Marcus Y Chin, Audrey Cheuk-Nga Ho, Rajarshi Ghosh, Dara E Leto, David Joy, Meredith E K Calvert, Joseph W Lewcock, Gilbert Di Paolo, Robert G Thorne, Zachary K Sweeney, Anastasia G Henry.
      Leucine-rich repeat kinase 2 (LRRK2) variants associated with Parkinson's disease (PD) and Crohn's disease lead to increased phosphorylation of its Rab substrates. While it has been recently shown that perturbations in cellular homeostasis including lysosomal damage can increase LRRK2 activity and localization to lysosomes, the molecular mechanisms by which LRRK2 activity is regulated have remained poorly defined. We performed a targeted siRNA screen to identify regulators of LRRK2 activity and identified Rab12 as a novel modulator of LRRK2-dependent phosphorylation of one of its substrates, Rab10. Using a combination of imaging and immunopurification methods to isolate lysosomes, we demonstrated that Rab12 is actively recruited to damaged lysosomes and leads to a local and LRRK2-dependent increase in Rab10 phosphorylation. PD-linked variants, including LRRK2 R1441G and VPS35 D620N, lead to increased recruitment of LRRK2 to the lysosome and a local elevation in lysosomal levels of pT73 Rab10. Together, these data suggest a conserved mechanism by which Rab12, in response to damage or expression of PD-associated variants, facilitates the recruitment of LRRK2 and phosphorylation of its Rab substrate(s) at the lysosome.
    Keywords:  cell biology; human
    DOI:  https://doi.org/10.7554/eLife.87255
  3. Chembiochem. 2023 Oct 23. e202300579
    Inducin Triggers LC3-Lipidation and ESCRT-Mediated Lysosomal Membrane Repair.
    Dale Corkery, Andrei Ursu, Belén Lucas, Michael Grigalunas, Simon Kriegler, Rosario Oliva, Robert Dec, Sandra Koska, Axel Pahl, Sonja Sievers, Slava Ziegler, Roland Winter, Yaowen Wu, Herbert Waldmann.
      Lipidation of the LC3 protein has frequently been employed as a marker of autophagy. However, LC3-lipidation is also triggered by stimuli not related to canonical autophagy. Therefore, characterization of the driving parameters for LC3 lipidation is crucial to understanding the biological roles of LC3. We identified a pseudo-natural product, termed Inducin, that increases LC3 lipidation independently of canonical autophagy, impairs lysosomal function and rapidly recruits Galectin 3 to lysosomes. Inducin treatment promotes Endosomal Sorting Complex Required for Transport (ESCRT)-dependent membrane repair and transcription factor EB (TFEB)-dependent lysosome biogenesis ultimately leading to cell death.
    Keywords:  Biological activity; Endolysosomal membrane damage; LC3 lipidation; Lysosomal membrane permeabilization; Small molecule
    DOI:  https://doi.org/10.1002/cbic.202300579
  4. Cell. 2023 Oct 18. pii: S0092-8674(23)01081-4. [Epub ahead of print]
    Nutrient-regulated control of lysosome function by signaling lipid conversion.
    Michael Ebner, Dmytro Puchkov, Orestes López-Ortega, Pathma Muthukottiappan, Yanwei Su, Christopher Schmied, Silke Zillmann, Iryna Nikonenko, Jochen Koddebusch, Gillian L Dornan, Max T Lucht, Vonda Koka, Wonyul Jang, Philipp Alexander Koch, Alexander Wallroth, Martin Lehmann, Britta Brügger, Mario Pende, Dominic Winter, Volker Haucke.
      Lysosomes serve dual antagonistic functions in cells by mediating anabolic growth signaling and the catabolic turnover of macromolecules. How these janus-faced activities are regulated in response to cellular nutrient status is poorly understood. We show here that lysosome morphology and function are reversibly controlled by a nutrient-regulated signaling lipid switch that triggers the conversion between peripheral motile mTOR complex 1 (mTORC1) signaling-active and static mTORC1-inactive degradative lysosomes clustered at the cell center. Starvation-triggered relocalization of phosphatidylinositol 4-phosphate (PI(4)P)-metabolizing enzymes reshapes the lysosomal surface proteome to facilitate lysosomal proteolysis and to repress mTORC1 signaling. Concomitantly, lysosomal phosphatidylinositol 3-phosphate (PI(3)P), which marks motile signaling-active lysosomes in the cell periphery, is erased. Interference with this PI(3)P/PI(4)P lipid switch module impairs the adaptive response of cells to altering nutrient supply. Our data unravel a key function for lysosomal phosphoinositide metabolism in rewiring organellar membrane dynamics in response to cellular nutrient status.
    Keywords:  catabolism; functional proteomics; live correlative light and electron microscopy; lysosomes; mTOR; myotubularin; nutrient signaling; nutrients; phosphoinositides
    DOI:  https://doi.org/10.1016/j.cell.2023.09.027
  5. PLoS Biol. 2023 Oct 23. 21(10): e3002337
    Spatacsin regulates directionality of lysosome trafficking by promoting the degradation of its partner AP5Z1.
    Alexandre Pierga, Raphaël Matusiak, Margaux Cauhapé, Julien Branchu, Lydia Danglot, Maxime Boutry, Frédéric Darios.
      The endoplasmic reticulum (ER) forms contacts with the lysosomal compartment, regulating lysosome positioning and motility. The movements of lysosomes are controlled by the attachment of molecular motors to their surface. However, the molecular mechanisms by which ER controls lysosome dynamics are still elusive. Here, using mouse brain extracts and mouse embryonic fibroblasts, we demonstrate that spatacsin is an ER-resident protein regulating the formation of tubular lysosomes, which are highly dynamic. Screening for spatacsin partners required for tubular lysosome formation showed spatacsin to act by regulating protein degradation. We demonstrate that spatacsin promotes the degradation of its partner AP5Z1, which regulates the relative amount of spastizin and AP5Z1 at lysosomes. Spastizin and AP5Z1 contribute to regulate tubular lysosome formation, as well as their trafficking by interacting with anterograde and retrograde motor proteins, kinesin KIF13A and dynein/dynactin subunit p150Glued, respectively. Ultimately, investigations in polarized mouse cortical neurons in culture demonstrated that spatacsin-regulated degradation of AP5Z1 controls the directionality of lysosomes trafficking. Collectively, our results identify spatacsin as a protein regulating the directionality of lysosome trafficking.
    DOI:  https://doi.org/10.1371/journal.pbio.3002337
  6. bioRxiv. 2023 Oct 02. pii: 2023.10.02.560519. [Epub ahead of print]
    Lysosomal proteomics reveals mechanisms of neuronal apoE4-associated lysosomal dysfunction.
    Einar K Krogsaeter, Justin McKetney, Angelica Marquez, Zeynep Cakir, Erica Stevenson, Gwendolyn M Jang, Antara Rao, Anton Zhou, Yadong Huang, Nevan J Krogan, Danielle L Swaney.
      ApoE4 is the primary risk factor for Alzheimer's Disease. While apoE is primarily expressed by astrocytes, AD pathology including endosomal abnormalities and mitochondrial dysfunction first occurs in neurons. Lysosomes are poised at the convergence point between these features. We find that apoE4-expressing cells exhibit lysosomal alkalinization, reduced lysosomal proteolysis, and impaired mitophagy. To identify driving factors for this lysosomal dysfunction, we performed quantitative lysosomal proteome profiling. This revealed that apoE4 expression results in lysosomal depletion of Lgals3bp and accumulation of Tmed5 in both Neuro-2a cells and postmitotic human neurons. Modulating the expression of both proteins affected lysosomal function, with Tmed5 knockdown rescuing lysosomal alkalinization in apoE4 cells, and Lgals3bp knockdown causing lysosomal alkalinization and reduced lysosomal density in apoE3 cells. Taken together, our work reveals that apoE4 exerts gain-of-toxicity by alkalinizing the lysosomal lumen, pinpointing lysosomal Tmed5 accumulation and Lgals3bp depletion as apoE4-associated drivers for this phenotype.
    DOI:  https://doi.org/10.1101/2023.10.02.560519
  7. Int J Mol Sci. 2023 Oct 11. pii: 15078. [Epub ahead of print]24(20):
    mTORC1 and SGLT2 Inhibitors-A Therapeutic Perspective for Diabetic Cardiomyopathy.
    Sumit Saha, Xianjun Fang, Christopher D Green, Anindita Das.
      Diabetic cardiomyopathy is a critical diabetes-mediated co-morbidity characterized by cardiac dysfunction and heart failure, without predisposing hypertensive or atherosclerotic conditions. Metabolic insulin resistance, promoting hyperglycemia and hyperlipidemia, is the primary cause of diabetes-related disorders, but ambiguous tissue-specific insulin sensitivity has shed light on the importance of identifying a unified target paradigm for both the glycemic and non-glycemic context of type 2 diabetes (T2D). Several studies have indicated hyperactivation of the mammalian target of rapamycin (mTOR), specifically complex 1 (mTORC1), as a critical mediator of T2D pathophysiology by promoting insulin resistance, hyperlipidemia, inflammation, vasoconstriction, and stress. Moreover, mTORC1 inhibitors like rapamycin and their analogs have shown significant benefits in diabetes and related cardiac dysfunction. Recently, FDA-approved anti-hyperglycemic sodium-glucose co-transporter 2 inhibitors (SGLT2is) have gained therapeutic popularity for T2D and diabetic cardiomyopathy, even acknowledging the absence of SGLT2 channels in the heart. Recent studies have proposed SGLT2-independent drug mechanisms to ascertain their cardioprotective benefits by regulating sodium homeostasis and mimicking energy deprivation. In this review, we systematically discuss the role of mTORC1 as a unified, eminent target to treat T2D-mediated cardiac dysfunction and scrutinize whether SGLT2is can target mTORC1 signaling to benefit patients with diabetic cardiomyopathy. Further studies are warranted to establish the underlying cardioprotective mechanisms of SGLT2is under diabetic conditions, with selective inhibition of cardiac mTORC1 but the concomitant activation of mTORC2 (mTOR complex 2) signaling.
    Keywords:  AMPK; SGLT2i; diabetes; diabetic cardiomyopathy; mTORC1/2
    DOI:  https://doi.org/10.3390/ijms242015078
  8. JACC Case Rep. 2023 Oct 18. 24 102023
    Distinguishing Lysosomal Acid Lipase Deficiency From Familial Hypercholesterolemia.
    Sohum Sheth, Peter P Toth, Seth J Baum, Monica Aggarwal.
      Lysosomal acid lipase deficiency (LAL-D) is underrecognized because it manifests clinically with lipid and lipoprotein values similar to those observed in heterozygous familial hypercholesterolemia (FH). Although LAL-D is uncommon, understanding the differences between the 2 diseases has significant management implications. We present a case of LAL-D that masqueraded as FH. (Level of Difficulty: Advanced.).
    Keywords:  familial hypercholesterolemia; low-density lipoprotein cholesterol; lysosomal acid lipase deficiency; sebelipase alfa
    DOI:  https://doi.org/10.1016/j.jaccas.2023.102023
This page is being maintained by Thomas Krichel. It was last updated on 2023‒10‒29 at 2:03.