{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,23]],"date-time":"2026-10-23T19:15:22Z","timestamp":1792782922229,"version":"4.5.0"},"reference-count":27,"publisher":"Springer Science and Business Media LLC","issue":"5-6","license":[{"start":{"date-parts":[[2022,4,18]],"date-time":"2022-04-18T00:00:00Z","timestamp":1650240000000},"content-version":"tdm","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0"},{"start":{"date-parts":[[2022,4,18]],"date-time":"2022-04-18T00:00:00Z","timestamp":1650240000000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0"}],"funder":[{"DOI":"10.13039\/501100001809","name":"National Natural Science Foundation of China","doi-asserted-by":"publisher","award":["82072226"],"award-info":[{"award-number":["82072226"]}],"id":[{"id":"10.13039\/501100001809","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100009592","name":"Beijing Municipal Science and Technology Commission","doi-asserted-by":"crossref","award":["Z201100005520049"],"award-info":[{"award-number":["Z201100005520049"]}],"id":[{"id":"10.13039\/501100009592","id-type":"DOI","asserted-by":"crossref"}]},{"name":"Tibet Natural Science Foundation","award":["XZ2019ZR-ZY12(Z)"],"award-info":[{"award-number":["XZ2019ZR-ZY12(Z)"]}]}],"content-domain":{"domain":["link.springer.com"],"crossmark-restriction":false},"short-container-title":["Apoptosis"],"published-print":{"date-parts":[[2022,6]]},"abstract":"<jats:title>Abstract<\/jats:title>\n                  <jats:p>Autophagy dysfunction contributes to CD4\u2009+\u2009T cell apoptosis during sepsis leading to impairment of adaptive immunity. However, the underlying mechanism is unclear. The mammalian target of rapamycin (mTOR) pathway modulates CD4\u2009+\u2009T cell survival during sepsis through mechanisms that are not fully understood. We developed a mouse model of sepsis through cecal ligation and puncture (CLP) to investigate dynamic changes in autophagy in CD4\u2009+\u2009T cells. We used T cell specific-mTOR\/tuberous sclerosis complex 1 (TSC1)-knockout mice to explore the roles of the mTOR pathway in modulating autophagy during sepsis. We observed reduced fusion of autophagosomes with lysosomes in the CD4\u2009+\u2009T cells of CLP mice, which may represent a characteristic feature of autophagy dysfunction. Deletion of mTOR relieved autophagosome-lysosome fusion dysfunction and ameliorated apoptosis of CD4\u2009+\u2009T cells in CLP mice, but this rescued phenotype was abolished by treatment with bafilomycin A1, a specific A-L fusion inhibitor. We further explored the underlying molecular mechanism and found that phosphorylation levels of transcription factor EB were significant higher in CLP mice and that expression of A-L fusion protein SNAREs were restricted, both of which were ameliorated by mTOR deletion. Taken together, these results suggest that the mTOR pathway plays a critical role in regulation of CD4\u2009+\u2009T-cell apoptosis during sepsis, partly through regulation of A-L fusion-related protein transcription.<\/jats:p>","DOI":"10.1007\/s10495-022-01719-y","type":"journal-article","created":{"date-parts":[[2022,4,18]],"date-time":"2022-04-18T07:12:49Z","timestamp":1650265969000},"page":"401-408","update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":26,"title":["mTOR deletion ameliorates CD4\u2009+\u2009T cell apoptosis during sepsis by improving autophagosome-lysosome fusion"],"prefix":"10.1007","volume":"27","author":[{"given":"Hao","family":"Wang","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Guangxu","family":"Bai","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jianwei","family":"Chen","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Wen","family":"Han","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ran","family":"Guo","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-1128-9228","authenticated-orcid":false,"given":"Na","family":"Cui","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2022,4,18]]},"reference":[{"issue":"8","key":"1719_CR1","doi-asserted-by":"publisher","first-page":"801","DOI":"10.1001\/jama.2016.0287","volume":"315","author":"M Singer","year":"2016","unstructured":"Singer M et al (2016) The Third International Consensus Definitions for Sepsis and Septic Shock (Sepsis-3). JAMA 315(8):801\u2013810","journal-title":"JAMA"},{"issue":"10219","key":"1719_CR2","doi-asserted-by":"publisher","first-page":"200","DOI":"10.1016\/S0140-6736(19)32989-7","volume":"395","author":"KE Rudd","year":"2020","unstructured":"Rudd KE et al (2020) Global, regional, and national sepsis incidence and mortality, 1990\u20132017: analysis for the Global Burden of Disease Study. The Lancet 395(10219):200\u2013211","journal-title":"The Lancet"},{"issue":"12","key":"1719_CR3","doi-asserted-by":"publisher","first-page":"e422","DOI":"10.1016\/S1473-3099(19)30567-5","volume":"19","author":"I Rubio","year":"2019","unstructured":"Rubio I et al (2019) Current gaps in sepsis immunology: new opportunities for translational research. Lancet Infect Dis 19(12):e422\u2013e436","journal-title":"Lancet Infect Dis"},{"issue":"3","key":"1719_CR4","doi-asserted-by":"publisher","first-page":"260","DOI":"10.1016\/S1473-3099(13)70001-X","volume":"13","author":"RS Hotchkiss","year":"2013","unstructured":"Hotchkiss RS, Monneret G, Payen D (2013) Immunosuppression in sepsis: a novel understanding of the disorder and a new therapeutic approach. Lancet Infect Dis 13(3):260\u2013268","journal-title":"Lancet Infect Dis"},{"issue":"2","key":"1719_CR5","doi-asserted-by":"publisher","first-page":"121","DOI":"10.1038\/nrneph.2017.165","volume":"14","author":"F Venet","year":"2018","unstructured":"Venet F, Monneret G (2018) Advances in the understanding and treatment of sepsis-induced immunosuppression. Nat Rev Nephrol 14(2):121\u2013137","journal-title":"Nat Rev Nephrol"},{"issue":"11","key":"1719_CR6","doi-asserted-by":"publisher","first-page":"6952","DOI":"10.4049\/jimmunol.166.11.6952","volume":"166","author":"RS Hotchkiss","year":"2001","unstructured":"Hotchkiss RS et al (2001) Sepsis-induced apoptosis causes progressive profound depletion of B and CD4 + T lymphocytes in humans. J Immunol 166(11):6952\u20136963","journal-title":"J Immunol"},{"issue":"2","key":"1719_CR7","doi-asserted-by":"publisher","first-page":"274","DOI":"10.1016\/j.cell.2012.03.017","volume":"149","author":"M Laplante","year":"2012","unstructured":"Laplante M, Sabatini DM (2012) mTOR signaling in growth control and disease. Cell 149(2):274\u2013293","journal-title":"Cell"},{"issue":"5","key":"1719_CR8","doi-asserted-by":"publisher","first-page":"730","DOI":"10.1016\/j.immuni.2017.04.028","volume":"46","author":"RG Jones","year":"2017","unstructured":"Jones RG, Pearce EJ (2017) MenTORing Immunity: mTOR Signaling in the Development and Function of Tissue-Resident Immune Cells. Immunity 46(5):730\u2013742","journal-title":"Immunity"},{"key":"1719_CR9","doi-asserted-by":"publisher","first-page":"4696","DOI":"10.1038\/ncomms5696","volume":"5","author":"L Zhu","year":"2014","unstructured":"Zhu L et al (2014) TSC1 controls macrophage polarization to prevent inflammatory disease. Nat Commun 5:4696","journal-title":"Nat Commun"},{"issue":"1","key":"1719_CR10","doi-asserted-by":"publisher","first-page":"15","DOI":"10.1111\/imr.12845","volume":"295","author":"H Huang","year":"2020","unstructured":"Huang H et al (2020) mTOR signaling at the crossroads of environmental signals and T-cell fate decisions. Immunol Rev 295(1):15\u201338","journal-title":"Immunol Rev"},{"issue":"5","key":"1719_CR11","doi-asserted-by":"publisher","first-page":"325","DOI":"10.1038\/nri3198","volume":"12","author":"H Chi","year":"2012","unstructured":"Chi H (2012) Regulation and function of mTOR signalling in T cell fate decisions. Nat Rev Immunol 12(5):325\u2013338","journal-title":"Nat Rev Immunol"},{"issue":"6","key":"1719_CR12","doi-asserted-by":"publisher","first-page":"2053","DOI":"10.1002\/hep.24324","volume":"53","author":"EH Carchman","year":"2011","unstructured":"Carchman EH et al (2011) Heme oxygenase-1-mediated autophagy protects against hepatocyte cell death and hepatic injury from infection\/sepsis in mice. Hepatology 53(6):2053\u20132062","journal-title":"Hepatology"},{"issue":"20","key":"1719_CR13","doi-asserted-by":"publisher","first-page":"2247","DOI":"10.1161\/CIRCULATIONAHA.117.032821","volume":"138","author":"Y Sun","year":"2018","unstructured":"Sun Y et al (2018) Beclin-1-Dependent Autophagy Protects the Heart During Sepsis. Circulation 138(20):2247\u20132262","journal-title":"Circulation"},{"key":"1719_CR14","doi-asserted-by":"publisher","first-page":"297","DOI":"10.1146\/annurev-physiol-021119-034658","volume":"82","author":"ME Choi","year":"2020","unstructured":"Choi ME (2020) Autophagy in Kidney Disease. Annu Rev Physiol 82:297\u2013322","journal-title":"Annu Rev Physiol"},{"issue":"2","key":"1719_CR15","doi-asserted-by":"publisher","first-page":"426","DOI":"10.1007\/s10753-018-00952-5","volume":"42","author":"H Zhao","year":"2019","unstructured":"Zhao H et al (2019) Autophagy Activation Improves Lung Injury and Inflammation in Sepsis. Inflammation 42(2):426\u2013439","journal-title":"Inflammation"},{"key":"1719_CR16","doi-asserted-by":"crossref","unstructured":"Tian X, Teng J, Chen J (2021 Oct) New insights regarding SNARE proteins in autophagosome-lysosome fusion. Autophagy 17(10):2680\u20132688","DOI":"10.1080\/15548627.2020.1823124"},{"issue":"7","key":"1719_CR17","doi-asserted-by":"publisher","first-page":"e102066","DOI":"10.1371\/journal.pone.0102066","volume":"9","author":"CW Lin","year":"2014","unstructured":"Lin CW et al (2014) T-cell autophagy deficiency increases mortality and suppresses immune responses after sepsis. PLoS ONE 9(7):e102066","journal-title":"PLoS ONE"},{"key":"1719_CR18","doi-asserted-by":"crossref","unstructured":"Fortunato F et al (2009) Impaired autolysosome formation correlates with Lamp-2 depletion: role of apoptosis, autophagy, and necrosis in pancreatitis. Gastroenterology, 137(1): p. 350 \u2013 60, 360.e1\u20135.","DOI":"10.1053\/j.gastro.2009.04.003"},{"issue":"1","key":"1719_CR19","doi-asserted-by":"publisher","first-page":"31","DOI":"10.1038\/nprot.2008.214","volume":"4","author":"D Rittirsch","year":"2009","unstructured":"Rittirsch D et al (2009) Immunodesign of experimental sepsis by cecal ligation and puncture. Nat Protoc 4(1):31\u201336","journal-title":"Nat Protoc"},{"issue":"7","key":"1719_CR20","doi-asserted-by":"crossref","first-page":"4148","DOI":"10.4049\/jimmunol.162.7.4148","volume":"162","author":"RS Hotchkiss","year":"1999","unstructured":"Hotchkiss RS et al (1999) Overexpression of Bcl-2 in transgenic mice decreases apoptosis and improves survival in sepsis. J Immunol 162(7):4148\u20134156","journal-title":"J Immunol"},{"issue":"2","key":"1719_CR21","doi-asserted-by":"publisher","first-page":"167","DOI":"10.1016\/j.molcel.2013.12.014","volume":"53","author":"V Rogov","year":"2014","unstructured":"Rogov V et al (2014) Interactions between autophagy receptors and ubiquitin-like proteins form the molecular basis for selective autophagy. Mol Cell 53(2):167\u2013178","journal-title":"Mol Cell"},{"key":"1719_CR22","doi-asserted-by":"crossref","unstructured":"Long J et al (2020) Notch signaling protects CD4 T cells from STING-mediated apoptosis during acute systemic inflammation. Sci Adv, 6(39)","DOI":"10.1126\/sciadv.abc5447"},{"issue":"4","key":"1719_CR23","doi-asserted-by":"publisher","first-page":"R160","DOI":"10.1186\/cc12839","volume":"17","author":"W Takahashi","year":"2013","unstructured":"Takahashi W et al (2013) Kinetics and protective role of autophagy in a mouse cecal ligation and puncture-induced sepsis. Crit Care 17(4):R160","journal-title":"Crit Care"},{"issue":"1","key":"1719_CR24","doi-asserted-by":"publisher","first-page":"e77","DOI":"10.1097\/CCM.0000000000002016","volume":"45","author":"T Oami","year":"2017","unstructured":"Oami T et al (2017) Suppression of T Cell Autophagy Results in Decreased Viability and Function of T Cells Through Accelerated Apoptosis in a Murine Sepsis Model. Crit Care Med 45(1):e77\u2013e85","journal-title":"Crit Care Med"},{"issue":"6","key":"1719_CR25","doi-asserted-by":"publisher","first-page":"1256","DOI":"10.1016\/j.cell.2012.11.001","volume":"151","author":"E Itakura","year":"2012","unstructured":"Itakura E, Kishi-Itakura C, Mizushima N (2012) The hairpin-type tail-anchored SNARE syntaxin 17 targets to autophagosomes for fusion with endosomes\/lysosomes. Cell 151(6):1256\u20131269","journal-title":"Cell"},{"issue":"13","key":"1719_CR26","doi-asserted-by":"crossref","first-page":"2475","DOI":"10.1242\/jcs.146365","volume":"129","author":"G Napolitano","year":"2016","unstructured":"Napolitano G, Ballabio A (2016) TFEB at a glance. J Cell Sci 129(13):2475\u20132481","journal-title":"J Cell Sci"},{"issue":"1","key":"1719_CR27","doi-asserted-by":"publisher","first-page":"3312","DOI":"10.1038\/s41467-018-05862-6","volume":"9","author":"G Napolitano","year":"2018","unstructured":"Napolitano G et al (2018) mTOR-dependent phosphorylation controls TFEB nuclear export. Nat Commun 9(1):3312","journal-title":"Nat Commun"}],"container-title":["Apoptosis"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/link.springer.com\/content\/pdf\/10.1007\/s10495-022-01719-y.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/link.springer.com\/article\/10.1007\/s10495-022-01719-y\/fulltext.html","content-type":"text\/html","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/link.springer.com\/content\/pdf\/10.1007\/s10495-022-01719-y.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2024,9,22]],"date-time":"2024-09-22T07:04:58Z","timestamp":1726988698000},"score":1,"resource":{"primary":{"URL":"https:\/\/link.springer.com\/10.1007\/s10495-022-01719-y"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2022,4,18]]},"references-count":27,"journal-issue":{"issue":"5-6","published-print":{"date-parts":[[2022,6]]}},"alternative-id":["1719"],"URL":"https:\/\/doi.org\/10.1007\/s10495-022-01719-y","relation":{},"ISSN":["1360-8185","1573-675X"],"issn-type":[{"value":"1360-8185","type":"print"},{"value":"1573-675X","type":"electronic"}],"subject":[],"published":{"date-parts":[[2022,4,18]]},"assertion":[{"value":"21 February 2022","order":1,"name":"accepted","label":"Accepted","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"18 April 2022","order":2,"name":"first_online","label":"First Online","group":{"name":"ArticleHistory","label":"Article History"}},{"order":1,"name":"Ethics","group":{"name":"EthicsHeading","label":"Declarations"}},{"value":"The study was conducted according to the guidelines of the Declaration of Helsinki, and approved by the Institutional Review Board of Peking Union Medical College Hospital, Chinese academy of medical sciences (Beijing, China). and the approval No is JS-1170.","order":2,"name":"Ethics","group":{"name":"EthicsHeading","label":"Institutional Review Board Statement"}},{"value":"The authors declare no conflict of interest.","order":3,"name":"Ethics","group":{"name":"EthicsHeading","label":"Conflict of interest"}}]}}