bims-nocaut 2025-04-06 papers

bims-nocaut

Biomed News

on Non-canonical autophagy

Issue of 2025–04–06
five papers selected by
Quentin Frenger, University of Strasbourg

HEATR3 recognizes membrane rupture and facilitates xenophagy in response to Salmonella invasion.
Type I interferons induce guanylate-binding proteins and lysosomal defense in hepatocytes to control malaria.
Lysyl-tRNA synthetase 1 promotes atherogenesis via autophagy-related secretion and inflammation.
Targeting of Lysosomes as a Therapeutic Target in Cancer.
Autophagy-related protein Atg11 is essential for microtubule-mediated chromosome segregation.

Proc Natl Acad Sci U S A. 2025 Apr 08. 122(14): e2420544122

HEATR3 recognizes membrane rupture and facilitates xenophagy in response to Salmonella invasion.

Masashi Arakawa, Keiya Uriu, Koki Saito, Mai Hirose, Kaoru Katoh, Krisana Asano, Akio Nakane, Tatsuya Saitoh, Tamotsu Yoshimori, Eiji Morita.

  Bacterial invasion into the cytoplasm of epithelial cells triggers the activation of the cellular autophagic machinery as a defense mechanism, a process known as xenophagy. In this study, we identified HEATR3, an LC3-interacting region (LIR)-containing protein, as a factor involved in this defense mechanism using quantitative mass spectrometry analysis. HEATR3 localizes intracellularly invading Salmonella, and HEATR3 deficiency promotes Salmonella proliferation in the cytoplasm. HEATR3 also localizes to lysosomes damaged by chemical treatment, suggesting that Salmonella recognition is facilitated by damage to the host cell membrane. HEATR3 deficiency impairs LC3 recruitment to damaged membranes and blocks the delivery of the target to the lysosome. These phenotypes were rescued by exogenous expression of wild-type HEATR3 but not by the LIR mutant, indicating the crucial role of the HEATR3-LC3 interaction in the receptor for selective autophagy. HEATR3 is delivered to lysosomes in an autophagy-dependent manner. Although HEATR3 recruitment to the damaged membrane was unaffected by ATG5 or FIP200 deficiency, it was markedly impaired by treatment with a calcium chelator, suggesting involvement upstream of the autophagic pathway. These findings suggest that HEATR3 serves as a receptor for selective autophagy and is able to identify damaged membranes, facilitate the removal of damaged lysosomes, and target invading bacteria within cells.

Keywords:  HEATR3; NOD2 signaling; autophagy; salmonella infection; xenophagy receptor

DOI:  https://doi.org/10.1073/pnas.2420544122
Cell Host Microbe. 2025 Mar 25. pii: S1931-3128(25)00091-5. [Epub ahead of print]

Type I interferons induce guanylate-binding proteins and lysosomal defense in hepatocytes to control malaria.

Camila Marques-da-Silva, Clyde Schmidt-Silva, Carson Bowers, Nana Appiah Essel Charles-Chess, Cristina Samuel, Justine C Shiau, Eui-Soon Park, Zhongyu Yuan, Bae-Hoon Kim, Dennis E Kyle, John T Harty, John D MacMicking, Samarchith P Kurup.

  Plasmodium parasites undergo development and replication within hepatocytes before infecting erythrocytes and initiating clinical malaria. Although type I interferons (IFNs) are known to hinder Plasmodium infection within the liver, the underlying mechanisms remain unclear. Here, we describe two IFN-I-driven hepatocyte antimicrobial programs controlling liver-stage malaria. First, oxidative defense by NADPH oxidases 2 and 4 triggers a pathway of lysosomal fusion with the parasitophorous vacuole (PV) to help clear Plasmodium. Second, guanylate-binding protein (GBP) 1-mediated disruption of the PV activates the caspase-1 inflammasome, inducing pyroptosis to remove infected host cells. Remarkably, both human and mouse hepatocytes enlist these cell-autonomous immune programs to eliminate Plasmodium, with their pharmacologic or genetic inhibition leading to profound malarial susceptibility in vivo. In addition to identifying IFN-I-mediated cell-autonomous immune circuits controlling Plasmodium infection in the hepatocytes, our study also extends the understanding of how non-immune cells are integral to protective immunity against malaria.

Keywords:  LAP; LC3; Plasmodium; cell-autonomous; cell-intrinsic; guanylate-binding protein; innate; liver; lysosome; malaria; reactive oxygen species

DOI:  https://doi.org/10.1016/j.chom.2025.03.008
Sci Rep. 2025 Apr 01. 15(1): 11099

Lysyl-tRNA synthetase 1 promotes atherogenesis via autophagy-related secretion and inflammation.

Kangmin Yun, Youngsik Seo, Yerim Oh, Sunghyen Kim, Hye Sun Maeng, Jin Gu Cho, Young Bae Son, Dong Ju Son, Kihwan Kwon, Sunghoon Kim, Hanjoong Jo, Heonyong Park.

  Lysyl-tRNA synthetase 1 (KARS1), an aminoacyl-tRNA synthetase, was recently identified as a secreted pro-inflammatory agent. However, the vascular secretion and functions of KARS1 have not been characterized. This study investigated the secretion mechanisms of KARS1 and explored its functional roles in vascular biology. We found that KARS1 expression was upregulated by oscillatory shear stress, an atherogenic factor, suggesting the presence of free KARS1 dissociated from aminoacyl-tRNA synthetase complexes. Moreover, in the presence of Ca2+, serum starvation triggered free cytosolic KARS1 release from endothelial cells via secretory autophagy. Both phosphatidylinositol 3-phosphate kinase and caveolin-1 were either supplementary or essential for KARS1 secretion. Secreted KARS1 co-localized in the exosome fraction of post-culture media and was externally exposed. Further, secreted KARS1 inhibited shear-induced activation of various signaling molecules, including extracellular signal-regulated kinase, protein kinase B, and endothelial nitric oxide synthetase. Secreted KARS1 in atherosclerotic plaques also acted as an atherogenic or proinflammatory autocrine/paracrine molecule. Additionally, KARS1 participated in vessel alteration. Collectively, these findings describe novel vascular features of KARS1 in response to shear stress, providing insights into shear stress-controlling mechanisms of the vascular system.

Keywords:  Cell apoptosis; KARS1; Laminar shear stress; Oscillatory shear stress; Secretory autophagy; Vessel alteration

DOI:  https://doi.org/10.1038/s41598-025-96046-y
Curr Mol Pharmacol. 2025 Apr 03.

Targeting of Lysosomes as a Therapeutic Target in Cancer.

Biyu Liu, Chengsheng Yang, Jiayi Liu, Minzhi Peng, Junquan Mao, Sanyuan Tang, Weiguo Huang.

  Lysosomes are important intracellular organelles involved in degradation metabolism, maintenance of homeostasis, cell survival and programmed death regulation, and play an important role in immunity. Some studies have shown that lysosomes are closely linked to tumor development. Lysosomes in tumor cells increase in size and activity to adapt to rapid proliferation. Cancer cells provide strong support for their unrestricted growth and proliferation by precisely regulating the number, composition and functional activities of lysosomes and also create favorable conditions for malignant behaviors such as survival, migration, invasion, and metastatic spread of cancer cells. Lysosomes play a central role in tumor progression, and in recent years, lysosomes have become an important target for anticancer strategies aimed at interfering with their function or modulating related signaling pathways to inhibit tumors. Current anti-cancer strategies include the following five aspects: (1) targeting tumor cell energy metabolism and lysosomes to inhibit growth; (2) inhibiting lysosomal histone proteases to block degradation metabolism; (3) destabilizing lysosomal membranes to trigger tumor cell death; (4) modulating lysosomal calcium signaling to affect tumor cell function; and (5) interfering with the mTOR signaling pathway to inhibit tumor growth and proliferation. These lysosome-targeted anticancer strategies offer broad prospects and potential for the development of novel anticancer drugs and therapies and are expected to bring more effective and safer therapeutic options for cancer patients.

Keywords:  Antitumor therapy; Autophagy.; Biological functions; Lysosome

DOI:  https://doi.org/10.2174/0118761429354659250320051057
PLoS Biol. 2025 Apr 02. 23(4): e3003069

Autophagy-related protein Atg11 is essential for microtubule-mediated chromosome segregation.

Md Hashim Reza, Rashi Aggarwal, Jigyasa Verma, Nitesh Kumar Podh, Ratul Chowdhury, Gunjan Mehta, Ravi Manjithaya, Kaustuv Sanyal.

Emerging studies hint at the roles of autophagy-related proteins in various cellular processes. To understand if autophagy-related proteins influence genome stability, we sought to examine a cohort of 35 autophagy mutants in Saccharomyces cerevisiae. We observe cells lacking Atg11 show poor mitotic stability of minichromosomes. Single-molecule tracking assays and live cell microscopy reveal that Atg11 molecules dynamically localize to the spindle pole bodies (SPBs) in a microtubule (MT)-dependent manner. Loss of Atg11 leads to a delayed cell cycle progression. Such cells accumulate at metaphase at an elevated temperature that is relieved when the spindle assembly checkpoint (SAC) is inactivated. Indeed, atg11∆ cells have stabilized securin levels, that prevent anaphase onset. Ipl1-mediated activation of SAC also confirms that atg11∆ mutants are defective in chromosome biorientation. Atg11 functions in the Kar9-dependent spindle positioning pathway. Stabilized Clb4 levels in atg11∆ cells suggest that Atg11 maintains Kar9 asymmetry by facilitating proper dynamic instability of astral microtubules (aMTs). Loss of Spc72 asymmetry contributes to non-random SPB inheritance in atg11∆ cells. Overall, this study uncovers an essential non-canonical role of Atg11 in the MT-mediated process of chromosome segregation.

DOI: https://doi.org/10.1371/journal.pbio.3003069