연구성과 홍보

Cell Mol Immunol. 2024 Dec;21(12):1441-1458.

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

Authors : Young Jae Kim#1,2, Sung-Gwon Lee#3,4, So Young Park#5, Sang Min Jeon1,2, Soo In Kim1,2, Kyung Tae Kim1,2,6, Taylor Roh1,2, Sang-Hee Lee7, Min Joung Lee2,6,8, Jinyoung Lee1,2, Hyeon Ji Kim1,2, So Eui Lee1,2, Jin Kyung Kim9, Jun Young Heo2,6,8, In Soo Kim2,10, Chungoo Park11*, Seungwha Paik12,13,14*, Eun-Kyeong Jo15,16*

Affiliations :

1Department of Microbiology, Chungnam National University College of Medicine, Daejeon, 35015, Republic of Korea.

2Department of Medical Science, Chungnam National University College of Medicine, Daejeon, 35015, Republic of Korea.

3Section 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.

4School of Biological Sciences and Technology, Chonnam National University, Gwangju, 61186, Republic of Korea.

5Division of Pulmonary, Allergy and Critical Care Medicine, Kangdong Sacred Heart Hospital, Hallym Medical Center, Seoul, 05355, Republic of Korea.

6System Network Inflammation Control Research Center, Chungnam National University College of Medicine, Daejeon, 35015, Republic of Korea.

7Center for Research Equipment, Korea Basic Science Institute, Cheongju, Chungbuk, 28199, Republic of Korea.

8Department of Biochemistry, Chungnam National University College of Medicine, Daejeon, 35015, Republic of Korea.

9Department of Microbiology, Keimyung University School of Medicine, Daegu, 42601, Republic of Korea.

10Department of Pharmacology, Chungnam National University College of Medicine, Daejeon, 35015, Republic of Korea.

11School of Biological Sciences and Technology, Chonnam National University, Gwangju, 61186, Republic of Korea. chungoo.park@gmail.com.

12Department of Microbiology, Chungnam National University College of Medicine, Daejeon, 35015, Republic of Korea. swpaik11@cnu.ac.kr.

13Department of Medical Science, Chungnam National University College of Medicine, Daejeon, 35015, Republic of Korea. swpaik11@cnu.ac.kr.

14System Network Inflammation Control Research Center, Chungnam National University College of Medicine, Daejeon, 35015, Republic of Korea.

15Department of Microbiology, Chungnam National University College of Medicine, Daejeon, 35015, Republic of Korea.

16Department of Medical Science, Chungnam National University College of Medicine, Daejeon, 35015, Republic of Korea.

DOI: 10.1038/s41423-024-01222-1.

Abstract :

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.