ArticleJournal of immunology (Baltimore, Md. : 1950)2018
mTORC2 Activity Disrupts Lysosome Acidification in Systemic Lupus Erythematosus by Impairing Caspase-1 Cleavage of Rab39a.
Article in Journal of immunology (Baltimore, Md. : 1950), 2018. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 18 papers.
What it found
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The abstract states no effect estimate the extractor could read, or names no intervention and outcome on the map, so this paper lights no cell and moves no belief. It is still indexed, cited and linked below.
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Trials whose registry record cites this paper, or whose number appears in the abstract. A trial that started after this paper was published is citing it as background, not reporting it.
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Who cites it
18 citing papers in PubMed, 22 citations in OpenAlex.
- TLR7/9 and type I interferon signaling reprogram neutrophil NET responses and impair antibacterial defense in systemic lupus erythematosus.Cell press blue · 2026Article
- Reduced late endosome/lysosome function promotes SLE through chronic PI3K activity and SHP-1/SHIP-1 defects.JCI insight · 2026Article
- Endosome traffic in rheumatic diseases: mechanistic insights and therapeutic opportunities.Nature reviews. Rheumatology · 2026Review
- A TLR7/9-IFNα-LDHB axis drives vital NET release and compromises antibacterial defense in lupus.bioRxiv : the preprint server for biology · 2025Article
- mTOR Signaling in Macrophages: All Depends on the Context.International journal of molecular sciences · 2025Review
- mTORC2 is crucial for regulating the recombinant Mycobacterium tuberculosis CFP-10 protein-induced phagocytosis in macrophages.BMC immunology · 2025Article
- Defective Lamtor5 Leads to Autoimmunity by Deregulating v-ATPase and Lysosomal Acidification.Advanced science (Weinheim, Baden-Wurttemberg, Germany) · 2024Article
- Cofilin-1 participates in the hyperfunction of myeloid dendritic cells in patients with severe aplastic anaemia.Journal of cellular and molecular medicine · 2022Article
- Altered Mitochondrial Homeostasis during Systemic Lupus Erythematosus Impairs Neutrophil Extracellular Trap Formation Rendering Neutrophils Ineffective at CombatingJournal of immunology (Baltimore, Md. : 1950) · 2022Article
- Hydroxychloroquine and COVID-19: a Rheumatologist's Take on the Lessons Learned.Current allergy and asthma reports · 2021Review
- The role of lysosome in regulated necrosis.Acta pharmaceutica Sinica. B · 2020Review
- Article
- The Arg/N-Degron Pathway-A Potential Running Back in Fine-Tuning the Inflammatory Response?Biomolecules · 2020Article
- Lysosomes as a therapeutic target.Nature reviews. Drug discovery · 2019Review
- Leptin signaling impairs macrophage defenses againstProceedings of the National Academy of Sciences of the United States of America · 2019Article
- The "other" mTOR complex: New insights into mTORC2 immunobiology and their implications.American journal of transplantation : official journal of the American Society of Transplantation and the American Society of Transplant Surgeons · 2019Review
- Lysosome: The metabolic signaling hub.Traffic (Copenhagen, Denmark) · 2019Review
- Article
Corrections and comments
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Authors and funding
9 authors at 1 institution in 2 countries.
Funding
Abstract
Lysosomes maintain immune homeostasis through the degradation of phagocytosed apoptotic debris; however, the signaling events regulating lysosomal maturation remain undefined. In this study, we show that lysosome acidification, key to the maturation process, relies on mTOR complex 2 (mTORC2), activation of caspase-1, and cleavage of Rab39a. Mechanistically, the localization of cofilin to the phagosome recruits caspase-11, which results in the localized activation of caspase-1. Caspase-1 subsequently cleaves Rab39a on the phagosomal membrane, promoting lysosome acidification. Although caspase-1 is critical for lysosome acidification, its activation is independent of inflammasomes and cell death mediated by apoptosis-associated speck-like protein containing a caspase recruitment domain, revealing a role beyond pyroptosis. In lupus-prone murine macrophages, chronic mTORC2 activity decouples the signaling pathway, leaving Rab39a intact. As a result, the lysosome does not acidify, and degradation is impaired, thereby heightening the burden of immune complexes that activate FcγRI and sustain mTORC2 activity. This feedforward loop promotes chronic immune activation, leading to multiple lupus-associated pathologies. In summary, these findings identify the key molecules in a previously unappreciated signaling pathway that promote lysosome acidification. It also shows that this pathway is disrupted in systemic lupus erythematosus.
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Registered trials
Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.