bims-lypmec 2025-01-12 papers

bims-lypmec

Biomed News

on Lysosomal positioning and metabolism in cardiomyocytes

Issue of 2025–01–12
six papers selected by
Satoru Kobayashi, New York Institute of Technology

Nonreceptor tyrosine kinase ABL1 regulates lysosomal acidification by phosphorylating the ATP6V1B2 subunit of the vacuolar-type H+-ATPase.
Serinc2 antagonizes pressure overload-induced cardiac hypertrophy via regulating the amino acid/mTORC1 signaling pathway.
Apolipoprotein-L Functions in Membrane Remodeling.
The role of multimodality imaging in diabetic cardiomyopathy: a brief review.
Cargo hitchhiking autophagy - a hybrid autophagy pathway utilized in yeast.
Chemically engineered antibodies for autophagy-based receptor degradation.

Autophagy. 2025 Jan 11. 1-20

Nonreceptor tyrosine kinase ABL1 regulates lysosomal acidification by phosphorylating the ATP6V1B2 subunit of the vacuolar-type H+-ATPase.

Caiwei Song, Qincai Dong, Yi Yao, Yan Cui, Chunmei Zhang, Lijun Lin, Lin Zhu, Yong Hu, Hainan Liu, Yanwen Jin, Ping Li, Xuan Liu, Cheng Cao.

  The vacuolar-type H+-ATPase (V-ATPase) is a proton pump responsible for controlling the intracellular and extracellular pH of cells. Its activity and assembly are tightly controlled by multiple pathways, of which phosphorylation-mediated regulation is poorly understood. In this report, we show that in response to starvation stimuli, the nonreceptor tyrosine kinase ABL1 directly interacts with ATP6V1B2, a subunit of the V1 domain of the V-ATPase, and phosphorylates ATP6V1B2 at Y68. Y68 phosphorylation in ATP6V1B2 facilitates the recruitment of the ATP6V1D subunit into the V1 subcomplex of V-ATPase, therefore potentiating the assembly of the V1 subcomplex with the membrane-embedded V0 subcomplex to form the integrated functional V-ATPase. ABL1 inhibition or depletion impairs V-ATPase assembly and lysosomal acidification, resulting in an increased lysosomal pH, a decreased lysosomal hydrolase activity, and consequently, the suppressed degradation of lumenal cargo during macroautophagy/autophagy. Consistently, the efficient removal of damaged mitochondrial residues during mitophagy is also impeded by ABL1 deficiency. Our findings suggest that ABL1 is a crucial autophagy regulator that maintains the adequate lysosomal acidification required for both physiological conditions and stress responses.Abbreviation: ANOVA: analysis of variance; Baf A1: bafilomycin A1; CCCP: carbonyl cyanide 3-chlorophenylhydrazone; CRK: CRK proto-oncogene, adaptor protein; CTSD: cathepsin D; DMSO: dimethylsulfoxide; EBSS: Earle's balanced salt solution; FITC: fluorescein isothiocyanate; GFP: green fluorescent protein; GST: glutathione S-transferase; LAMP2: lysosomal associated membrane protein 2; MAP1LC3/LC3: microtubule associated protein 1 light chain 3; MTORC1: mechanistic target of rapamycin kinase complex 1; PD: Parkinson disease; PLA: proximity ligation assay; RFP: red fluorescent protein; WT: wild-type.

Keywords:  ABL1; V-ATPase; kinase; lysosome; phosphorylation

DOI:  https://doi.org/10.1080/15548627.2024.2448913
Biochim Biophys Acta Mol Basis Dis. 2025 Jan 03. pii: S0925-4439(24)00644-6. [Epub ahead of print]1871(3): 167650

Serinc2 antagonizes pressure overload-induced cardiac hypertrophy via regulating the amino acid/mTORC1 signaling pathway.

Shuai Mao, Manqi Yang, Huimin Liu, Shun Wang, Man Liu, Shan Hu, Beilei Liu, Hao Ju, Zheyu Liu, Min Huang, Shuijing He, Mian Cheng, Gang Wu.

   BACKGROUND: Cardiac hypertrophy is characterized by the upregulation of fetal genes, increased protein synthesis, and enlargement of cardiac myocytes. The mechanistic target of rapamycin complex 1 (mTORC1), which responds to fluctuations in cellular nutrient and energy levels, plays a pivotal role in regulating protein synthesis and cellular growth. While attempts to inhibit mTORC1 activity, such as through the application of rapamycin and its analogs, have demonstrated limited efficacy, further investigation is warranted.
METHODS AND RESULTS: Here, we show that Serinc2 expression is downregulated in the transverse aortic constriction (TAC)-induced hypertrophic myocardium. Both in vivo and in vitro, the reduction of Serinc2 expression results in pathological hypertrophic growth, whereas Serinc2 overexpression exhibits a protective effect. RNA sequencing analysis following Serinc2 knockdown reveals a transcriptomic shift toward a pro-hypertrophic profile and suggests a significant interplay between Serinc2, amino acid, mTOR, and the lysosome, a hub for mTOR activation. Moreover, we show that Serinc2 localizes to lysosomes and hinders mTORC1 recruitment to the lysosomal membrane in response to amino acid stimulation, playing a critical role in regulating amino acid signaling pathway involved in the activation of p70S6K, S6, and 4EBP1 in Hela cells. And its deficiency exacerbates mTORC1 activity and mTORC1-dependent subsequent protein synthesis, which can be abrogated by rapamycin. In line with our in vitro findings, Serinc2 knockout mice subjected to TAC surgery exhibit elevated phosphorylation of p70S6K and 4EBP1, while inhibition of mTORC1 signaling through amino acid deprivation prevents this activation and impedes the progression to pathological cardiac remodeling.
CONCLUSIONS: We have illustrated that Serinc2 localizes to the lysosomal membrane and modulates amino acid /mTORC1 signaling in cardiomyocytes. Serinc2 therefore presents a potential therapeutic target for mitigating excessive protein synthesis and improving heart failure under hemodynamic stress.

Keywords:  Amino acid; Cardiac hypertrophy; Lysosome; SERINC2; mTORC1

DOI:  https://doi.org/10.1016/j.bbadis.2024.167650
Cells. 2024 Dec 20. pii: 2115. [Epub ahead of print]13(24):

Apolipoprotein-L Functions in Membrane Remodeling.

Etienne Pays.

  The mammalian Apolipoprotein-L families (APOLs) contain several isoforms of membrane-interacting proteins, some of which are involved in the control of membrane dynamics (traffic, fission and fusion). Specifically, human APOL1 and APOL3 appear to control membrane remodeling linked to pathogen infection. Through its association with Non-Muscular Myosin-2A (NM2A), APOL1 controls Golgi-derived trafficking of vesicles carrying the lipid scramblase Autophagy-9A (ATG9A). These vesicles deliver APOL3 together with phosphatidylinositol-4-kinase-B (PI4KB) and activated Stimulator of Interferon Genes (STING) to mitochondrion-endoplasmic reticulum (ER) contact sites (MERCSs) for the induction and completion of mitophagy and apoptosis. Through direct interactions with PI4KB and PI4KB activity controllers (Neuronal Calcium Sensor-1, or NCS1, Calneuron-1, or CALN1, and ADP-Ribosylation Factor-1, or ARF1), APOL3 controls PI(4)P synthesis. PI(4)P is required for different processes linked to infection-induced inflammation: (i) STING activation at the Golgi and subsequent lysosomal degradation for inflammation termination; (ii) mitochondrion fission at MERCSs for induction of mitophagy and apoptosis; and (iii) phagolysosome formation for antigen processing. In addition, APOL3 governs mitophagosome fusion with endolysosomes for mitophagy completion, and the APOL3-like murine APOL7C is involved in phagosome permeabilization linked to antigen cross-presentation in dendritic cells. Similarly, APOL3 can induce the fusion of intracellular bacterial membranes, and a role in membrane fusion can also be proposed for endothelial APOLd1 and adipocyte mAPOL6, which promote angiogenesis and adipogenesis, respectively, under inflammatory conditions. Thus, different APOL isoforms play distinct roles in membrane remodeling associated with inflammation.

Keywords:  APOL1 nephropathy; APOL1 risk variants; APOL3 antibacterial activity; adipogenesis; angiogenesis; antigen cross-presentation; kidney disease; membrane fission; membrane fusion; mitophagy

DOI:  https://doi.org/10.3390/cells13242115
Front Endocrinol (Lausanne). 2024 ;15 1405031

The role of multimodality imaging in diabetic cardiomyopathy: a brief review.

Fadi W Adel, Horng H Chen.

  Diabetic cardiomyopathy (DMCM), defined as left ventricular dysfunction in the setting of diabetes mellitus without hypertension, coronary artery disease or valvular heart disease, is a well-recognized entity whose prevalence is certainly predicted to increase alongside the rising incidence and prevalence of diabetes mellitus. The pathophysiology of DMCM stems from hyperglycemia and insulin resistance, resulting in oxidative stress, inflammation, cardiomyocyte death, and fibrosis. These perturbations lead to left ventricular hypertrophy with associated impaired relaxation early in the course of the disease, and eventually culminating in combined systolic and diastolic heart failure. Echocardiography, cardiac nuclear imaging, and cardiac magnetic resonance imaging are crucial in the diagnosis and management of the structural and functional changes associated with DMCM. There appears to be a U-shaped relationship between glycemic control and mortality. Exogenous insulin therapy, while crucial, has been identified as an independent risk factor for worsening cardiovascular outcomes. On the other hand, Glucagon-like Peptide-1 Receptor Agonists and Sodium-Glucose Cotransporter 2 Inhibitors appear to potentially offer glycemic control and cardiovascular protection. In this review, we briefly discuss the pathophysiology, staging, role of multimodality imaging, and therapeutics in DMCM.

Keywords:  cardiac MRI; cardiac nuclear imaging; diabetes mellitus; diabetes therapeutics; diabetic cardiomyopathy; echocardiography; heart failure; multi-modality imaging

DOI:  https://doi.org/10.3389/fendo.2024.1405031
Autophagy. 2025 Jan 05. 1-13

Cargo hitchhiking autophagy - a hybrid autophagy pathway utilized in yeast.

Katrina F Cooper.

  Macroautophagy is a catabolic process that maintains cellular homeostasis by recycling intracellular material through the use of double-membrane vesicles called autophagosomes. In turn, autophagosomes fuse with vacuoles (in yeast and plants) or lysosomes (in metazoans), where resident hydrolases degrade the cargo. Given the conservation of autophagy, Saccharomyces cerevisiae is a valuable model organism for deciphering molecular details that define macroautophagy pathways. In yeast, macroautophagic pathways fall into two subclasses: selective and nonselective (bulk) autophagy. Bulk autophagy is predominantly upregulated following TORC1 inhibition, triggered by nutrient stress, and degrades superfluous random cytosolic proteins and organelles. In contrast, selective autophagy pathways maintain cellular homeostasis when TORC1 is active by degrading damaged organelles and dysfunctional proteins. Here, selective autophagy receptors mediate cargo delivery to the vacuole. Now, two groups have discovered a new hybrid autophagy mechanism, coined cargo hitchhiking autophagy (CHA), that uses autophagic receptor proteins to deliver selected cargo to phagophores built in response to nutrient stress for the random destruction of cytosolic contents. In CHA, various autophagic receptors link their cargos to lipidated Atg8, located on growing phagophores. In addition, the sorting nexin heterodimer Snx4-Atg20 assists in the degradation of cargo during CHA, possibly by aiding the delivery of cytoplasmic cargos to phagophores and/or by delaying the closure of expanding phagophores. This review will outline this new mechanism, also known as Snx4-assisted autophagy, that degrades an assortment of cargos in yeast, including transcription factors, glycogen, and a subset of ribosomal proteins.

Keywords:  Atg45; Hab1; Ksp1; cargo hitchhiking autophagy; receptor proteins

DOI:  https://doi.org/10.1080/15548627.2024.2447207
Nat Chem Biol. 2025 Jan 09.

Chemically engineered antibodies for autophagy-based receptor degradation.

Binghua Cheng, Meiqing Li, Jiwei Zheng, Jiaming Liang, Yanyan Li, Ruijing Liang, Hui Tian, Zeyu Zhou, Li Ding, Jian Ren, Wenli Shi, Wenjie Zhou, Hailiang Hu, Long Meng, Ke Liu, Lintao Cai, Ximing Shao, Lijing Fang, Hongchang Li.

Cell surface receptor-targeted protein degraders hold promise for drug discovery. However, their application is restricted because of the complexity of creating bifunctional degraders and the reliance on specific lysosome-shuttling receptors or E3 ubiquitin ligases. To address these limitations, we developed an autophagy-based plasma membrane protein degradation platform, which we term AUTABs (autophagy-inducing antibodies). Through covalent conjugation with polyethylenimine (PEI), the engineered antibodies acquire the capacity to degrade target receptors through autophagy. The degradation activities of AUTABs are self-sufficient, without necessitating the participation of lysosome-shuttling receptors or E3 ubiquitin ligases. The broad applicability of this platform was then illustrated by targeting various clinically important receptors. Notably, combining specific primary antibodies with a PEI-tagged secondary nanobody also demonstrated effective degradation of target receptors. Thus, our study outlines a strategy for directing plasma membrane proteins for autophagic degradation, which possesses desirable attributes such as ease of generation, independence from cell type and broad applicability.

DOI: https://doi.org/10.1038/s41589-024-01803-1