bims-lypmec 2026-01-11 papers

J Cell Biol. 2026 Mar 02. pii: e202506139. [Epub ahead of print]225(3):

Plasma membrane-to-lysosome FGR signaling regulates endocytosis-associated lysosome homeostasis.

Qiuyuan Yin, Jifan Qian, Xiao Ding, Xiaoxia Ren, Shalan Li, Zonghao Zhang, Meijiao Li, Long Xiao, Zhiguo Zhang, Fan Lai, Xuna Wu, Xiaojiang Hao, Chonglin Yang.

Transcriptional control of lysosome biogenesis is an important mechanism underlying cellular adaptation to stress. It is largely unclear how cell surface changes or signals induce alteration in lysosome numbers. By developing a Caenorhabditis elegans-based heterologous TFE3 activation system, we here identify the non-receptor tyrosine kinases SRC-1/-2 (C. elegans) and FGR (mammals) as critical regulators of lysosome biogenesis. In C. elegans, inactivation of src-1/-2 leads to nuclear enrichment of ectopically expressed TFE3 and increased intensity of lysosomal markers. In mammalian cells, FGR inhibition or deficiency similarly results in TFEB/TFE3-dependent lysosomal increase. FGR acts through AKT2 by promoting the activation of the latter. FGR associates with the plasma membrane but is internalized onto endosomes and reaches lysosomes along the endosome-lysosome pathway following endocytosis. Lysosomal FGR promotes AKT2 recruitment to lysosomes, where it phosphorylates TFEB/TFE3 to prevent their activation. Together, these findings reveal a plasma membrane-to-lysosome signaling axis that is required for endocytosis-associated lysosome homeostasis.

DOI: https://doi.org/10.1083/jcb.202506139

Autophagy. 2026 Jan 04. 1-18

Measuring lysosome damage and lysophagy in vivo.

Zelai Wu, Hanyu Zhan, Zhiming Huang, Changjing Wang, Boran Li, Yepeng Hu, Zhida Chen, Wei Liu, Weihua Gong, Yongjuan Sang, Qiming Sun.

Lysosome homeostasis is vital for cellular fitness due to the essential roles of this organelle in various pathways. Given their extensive workload, lysosomes are prone to damage, which can stimulate lysosomal quality control mechanisms such as biogenesis, repair, or autophagic removal - a process termed lysophagy. Despite recent advances highlighting lysophagy as a critical mechanism for lysosome maintenance, the extent of lysosome integrity perturbation and the magnitude of lysophagy in vivo remain largely unexplored. Additionally, the pathophysiological relevance of lysophagy is poorly understood. To address these gaps, it is necessary to develop quantifiable methods for evaluating lysosome damage and lysophagy flux in vivo. To this end, we created two transgenic mouse lines expressing a tandem fluorescent LGALS3/galectin 3 probe (tfGAL3), either constitutively or conditionally under Cre recombinase control, utilizing the property of LGALS3 to recognize damaged lysosomes. This tool enables spatiotemporal visualization of lysosome damage and lysophagy activity at single-cell resolution in vivo. Systemic analysis across various organs, tissues, and primary cultures from these lysophagy reporter mice revealed significant variations in basal lysophagy, both in vivo and in vitro. Additionally, this study identified substantial changes in lysosome integrity and lysophagy flux in different tissues under stress conditions such as starvation, acute kidney injury and diabetic modeling. In conclusion, these complementary lysophagy reporter models are valuable resources for both basic and translational research.Abbreviation: AAV: adeno-associated virus; ATG7: autophagy related 7; CA-tfGAL3: cre-recombinase-activated tandem fluorescent LGALS3; DAPI: 4',6-diamidino-2-phenylindole; DM: diabetes mellitus; ESCRT: endosomal sorting complex required for transport; GFP: green fluorescent protein; HFD: high-fat diet; Igs2/H11/Hipp11: intergenic site 2; IST1: IST1 factor associated with ESCRT-III; KI: knock-in; LAMP1: lysosomal-associated membrane protein 1; LGALS3: lectin, galactoside-binding, soluble, 3; LLOMe: L-leucyl-L-leucine methyl ester hydrobromide; MEFs: mouse embryonic fibroblasts; NaOx: sodium oxalate; PDCD6IP: programmed cell death 6 interacting protein; PTECs: proximal tubular epithelial cells; RFP: red fluorescent protein; STZ: streptozotocin; TAM: tamoxifen; tfGAL3: tandem fluorescent LGALS3; TMEM192: transmembrane protein 192.

Keywords: In vivo; lysophagy; lysosome; lysosome damage; ratiometric probe

DOI: https://doi.org/10.1080/15548627.2025.2608974

EMBO J. 2026 Jan 03.

The ATG8 E3-like ligases sense lysosomal damage and initiate ESCRT-mediated membrane repair.

Dale P Corkery, Deerada Wijayatunga, Benedita K L Feron, Laura K Herzog, Anastasia Knyazeva, Yao-Wen Wu.

After damage from pathogenic, chemical or physical stress, endolysosomal membranes are repaired and resealed by the endosomal sorting complex required for transport (ESCRT) machinery, but how this membrane damage is sensed and translated into ESCRT recruitment is poorly understood. Here, we identify the two ATG8 E3-like ligases, ATG16L1 and TECPR1, as ion-dependent catalysts for ESCRT recruitment to damaged lysosomal membranes. Leakage from perforated lysosomes induces the proton sensitive V-ATPase-dependent recruitment of ATG16L1-ATG5-ATG12 complexes, or the calcium-sensitive sphingomyelin-dependent recruitment of TECPR1-ATG5-ATG12 complexes. In both cases, the E3-like complex-dependent ATG5-ATG12 conjugate is required for ESCRT recruitment to the damaged membrane, and stabilization of the ESCRT machinery. Collectively, this study establishes the ATG8 E3-like ligases as membrane damage sensors for ESCRT-mediated membrane repair.

Keywords: ATG8 E3-like Ligases; CASM; ESCRT; Lysosomal Membrane Integrity; Membrane Damage Sensor

DOI: https://doi.org/10.1038/s44318-025-00672-1

Cell. 2026 Jan 08. pii: S0092-8674(25)01418-7. [Epub ahead of print]

Structure of the lysosomal KICSTOR-GATOR1-SAMTOR nutrient-sensing supercomplex.

Christopher J Lupton, Charles Bayly-Jones, Shuqi Dong, Terrance Lam, Wentong Luo, Gareth D Jones, Chantel Mastos, Nicholas J Frescher, San S Lim, Alastair C Keen, Luke E Formosa, Hari Venugopal, Yong-Gang Chang, Michelle L Halls, Andrew M Ellisdon.

The guanosine triphosphate (GTP)-bound state of the heterodimeric Rag GTPases functions as a molecular switch regulating mechanistic target of rapamycin complex 1 (mTORC1) activation at the lysosome downstream of amino acid fluctuations. Under low amino acid conditions, GTPase-activating protein (GAP) activity toward Rags 1 (GATOR1) promotes RagA GTP hydrolysis, preventing mTORC1 activation. KICSTOR recruits and regulates GATOR1 at the lysosome by undefined mechanisms. Here, we resolve the KICSTOR-GATOR1 structure, revealing a striking ∼60-nm crescent-shaped assembly. GATOR1 anchors to KICSTOR via an extensive interface, and mutations that disrupt this interaction impair mTORC1 regulation. The S-adenosylmethionine sensor SAMTOR binds KICSTOR in a manner incompatible with metabolite binding, providing structural insight into methionine sensing via SAMTOR-KICSTOR association. We discover that KICSTOR and GATOR1 form a dimeric supercomplex. This assembly restricts GATOR1 to an orientation that favors the low-affinity active GAP mode of Rag GTPase engagement while sterically restricting access to the high-affinity inhibitory mode, consistent with a model of an active lysosomal GATOR1 docking complex.

Keywords: GATOR1; KICSTOR; RAG GTPase; Rag-Ragulator; S-adenosylmethionine; SAMTOR; SZT2; cell metabolism; cryo-EM; mTORC1

DOI: https://doi.org/10.1016/j.cell.2025.12.005

JACC Heart Fail. 2026 Jan;pii: S2213-1779(25)00329-4. [Epub ahead of print]14(1): 102460

"Arising" Above Heart Failure: Sex Differences in Diabetic Cardiomyopathy.

Ersilia M DeFilippis, Eileen O'Meara.

Keywords: diabetic cardiomyopathy; heart failure; obesity; sex differences

DOI: https://doi.org/10.1016/j.jchf.2025.03.021

Cell Death Dis. 2026 Jan 09. 17(1): 26

Loss of TMEM55B modulates lipid metabolism through dysregulated lipophagy and mitochondrial function.

Yuanyuan Qin, Sheila S Teker, Nilsa La Cunza, Yao Tong, Elizabeth Theusch, Neil V Yang, Leela Venkatesan, Julia Su, Xuanwen Wang, Ronald M Krauss, Aparna Lakkaraju, Aras N Mattis, Marisa W Medina.

Lipophagy is a form of selective autophagy that targets the lipid droplets for lysosomal decay and has been implicated in the onset and progression of metabolic dysfunction-associated steatotic liver disease (MASLD). Factors that augment lipophagy have been identified as targets for MASLD therapeutic development. TMEM55B is a key regulator of lysosomal positioning, which is critical for lysosome fusion with the autophagosome, but is less well studied. Here, we demonstrate that the absence of TMEM55B in murine models accelerates MASLD onset and progression to metabolic dysfunction-associated steatohepatitis (MASH). In cellular models, TMEM55B deficiency enhances incomplete lipophagy, whereby lysosome-lipid droplet interactions are increased, but lysosomal cargo is not fully degraded and/or released, leading to the development of lipid-filled lysosomes (lipolysosomes). Loss of TMEM55B also impairs mitophagy, causing an accumulation of dysfunctional mitochondria. This imbalance leads to increased lipid accumulation and oxidative stress, worsening MASLD. These findings underscore the importance of lysosomal positioning in lipid metabolism and suggest that targeting lipophagy for MASLD therapeutic development should be carefully considered to ensure promotion of the entire lipophagic flux pathway and whether it occurs in the context of mitochondrial dysfunction.

DOI: https://doi.org/10.1038/s41419-025-08210-x