Ubiquitin regulatory X(UBX)domain-containing protein 6 is essential for autophagy induction and inflammation control in macrophages  

作　　者：Young Jae Kim Sung-Gwon Lee So Young Park Sang Min Jeon Soo In Kim Kyung Tae Kim Taylor Roh Sang-Hee Lee Min Joung Lee Jinyoung Lee Hyeon Ji Kim So Eui Lee Jin Kyung Kim Jun Young Heo In Soo Kim Chungoo Park Seungwha Paik Eun-Kyeong Jo 

机构地区：[1]Department of Microbiology,Chungnam National University College of Medicine,Daejeon 35015,Republic of Korea [2]Department of Medical Science,Chungnam National University College of Medicine,Daejeon 35015,Republic of Korea [3]Section of Genetics and Physiology,Laboratory of Molecular and Cellular Biology,National Institute of Diabetes and Digestive and Kidney Diseases(NIDDK),National Institutes of Health(NIH),Bethesda,MD 20892,USA [4]School of Biological Sciences and Technology,Chonnam National University,Gwangju 61186,Republic of Korea [5]Division of Pulmonary,Allergy and Critical Care Medicine,Kangdong Sacred Heart Hospital,Hallym Medical Center,Seoul 05355,Republic of Korea [6]System Network Inflammation Control Research Center,Chungnam National University College of Medicine,Daejeon 35015,Republic of Korea [7]Center for Research Equipment,Korea Basic Science Institute,Cheongju,Chungbuk 28199,Republic of Korea [8]Department of Biochemistry,Chungnam National University College of Medicine,Daejeon 35015,Republic of Korea [9]Department of Microbiology,Keimyung University School of Medicine,Daegu 42601,Republic of Korea [10]Department of Pharmacology,Chungnam National University College of Medicine,Daejeon 35015,Republic of Korea

出　　处：《Cellular & Molecular Immunology》2024年第12期1441-1458,共18页中国免疫学杂志(英文版)

基　　金：supported by the National Research Foundation of Korea(NRF)grants funded by the Korea government(MSIT)(RS-2023-00255021,RS-2023-00227274,and RS-2024-00406568).

摘　　要：Ubiquitin regulatory X(UBX)domain-containing protein 6(UBXN6)is an essential cofactor for the activity of the valosin-containing protein p97,an adenosine triphosphatase associated with diverse cellular activities.Nonetheless,its role in cells of the innate immune system remains largely unexplored.In this study,we report that UBXN6 is upregulated in humans with sepsis and may serve as a pivotal regulator of inflammatory responses via the activation of autophagy.Notably,the upregulation of UBXN6 in sepsis patients was negatively correlated with inflammatory gene profiles but positively correlated with the expression of Forkhead box O3,an autophagy-driving transcription factor.Compared with those of control mice,the macrophages of mice subjected to myeloid cell-specific UBXN6 depletion exhibited exacerbated inflammation,increased mitochondrial oxidative stress,and greater impairment of autophagy and endoplasmic reticulum-associated degradation pathways.UBXN6-deficient macrophages also exhibited immunometabolic remodeling,characterized by a shift to aerobic glycolysis and elevated levels of branched-chain amino acids.These metabolic shifts amplify mammalian target of rapamycin pathway signaling,in turn reducing the nuclear translocation of the transcription factor EB and impairing lysosomal biogenesis.Together,these data reveal that UBXN6 serves as an activator of autophagy and regulates inflammation to maintain immune system suppression during human sepsis.

关 键 词：UBXN6 SEPSIS INFLAMMATION AUTOPHAGY Immunosuppressi 

分 类 号：R73[医药卫生—肿瘤]