Molecular mechanisms of snoRNA-IL-15 crosstalk in adipocyte lipolysis and NK cell rejuvenation

Yaohua Zhang; Zilong Zhao; Lisa A Huang; Yuan Liu; Jun Yao; Chengcao Sun; Yajuan Li; Zhao Zhang; Youqiong Ye; Fei Yuan; Tina K Nguyen; Nikhil Reddy Garlapati; Andrew Wu; Sergey D Egranov; Abigail S Caudle; Aysegul A Sahin; Bora Lim; Laura Beretta; George A Calin; Dihua Yu; Mien-Chie Hung; Michael A Curran; Katayoun Rezvani; Boyi Gan; Zhi Tan; Leng Han; Chunru Lin; Liuqing Yang

doi:10.1016/j.cmet.2023.05.009

Molecular mechanisms of snoRNA-IL-15 crosstalk in adipocyte lipolysis and NK cell rejuvenation

Cell Metab. 2023 Aug 8;35(8):1457-1473.e13. doi: 10.1016/j.cmet.2023.05.009. Epub 2023 Jun 16.

Authors

Yaohua Zhang¹, Zilong Zhao¹, Lisa A Huang¹, Yuan Liu², Jun Yao¹, Chengcao Sun¹, Yajuan Li¹, Zhao Zhang³, Youqiong Ye³, Fei Yuan⁴, Tina K Nguyen¹, Nikhil Reddy Garlapati¹, Andrew Wu¹, Sergey D Egranov¹, Abigail S Caudle⁵, Aysegul A Sahin⁶, Bora Lim⁷, Laura Beretta¹, George A Calin⁸, Dihua Yu⁹, Mien-Chie Hung¹⁰, Michael A Curran¹¹, Katayoun Rezvani¹², Boyi Gan¹³, Zhi Tan¹⁴, Leng Han¹⁵, Chunru Lin¹⁶, Liuqing Yang¹⁷

Affiliations

¹ Department of Molecular and Cellular Oncology, University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA.
² Center for Epigenetics and Disease Prevention, Institute of Biosciences and Technology, Texas A&M University, Houston, TX, USA.
³ Department of Biochemistry and Molecular Biology, University of Texas Health Science Center at Houston McGovern Medical School, Houston, TX 77030, USA.
⁴ Center for Drug Discovery, Department of Pathology & Immunology, Baylor College of Medicine, Houston, TX 77030, USA.
⁵ Department of Breast Surgical Oncology, Division of Surgery, University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA.
⁶ Department of Pathology, Division of Pathology and Laboratory Medicine, University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA.
⁷ Oncology/Medicine, Dan L. Duncan Comprehensive Cancer Center, Baylor College of Medicine, Houston, TX, USA.
⁸ Department of Translational Molecular Pathology, University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA; Center for RNA Interference and Non-Coding RNAs, University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA.
⁹ Department of Molecular and Cellular Oncology, University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA; Graduate School of Biomedical Sciences, University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA.
¹⁰ Graduate Institute of Biomedical Sciences, Institute of Biochemistry and Molecular Biology, Research Center for Cancer Biology, Cancer Biology and Precision Therapeutics Center, and Center for Molecular Medicine, China Medical University, Taichung 406, Taiwan.
¹¹ Graduate School of Biomedical Sciences, University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA; Department of Immunology, University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA.
¹² Graduate School of Biomedical Sciences, University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA; Department of Stem Cell Transplantation and Cellular Therapy, University of Texas MD Anderson Cancer Center, Houston, TX, USA.
¹³ Graduate School of Biomedical Sciences, University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA; Department of Experimental Radiation Oncology, Division of Radiation Oncology, University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA.
¹⁴ Center for Drug Discovery, Department of Pathology & Immunology, Baylor College of Medicine, Houston, TX 77030, USA; Department of Pharmacology and Chemical Biology, Baylor College of Medicine, Houston, TX 77030, USA. Electronic address: zhi.tan@bcm.edu.
¹⁵ Center for Epigenetics and Disease Prevention, Institute of Biosciences and Technology, Texas A&M University, Houston, TX, USA; Brown Center for Immunotherapy, School of Medicine, Indiana University, Indianapolis, IN 46202, USA; Department of Biostatistics and Health Data Science, School of Medicine, Indiana University, Indianapolis, IN 46202, USA. Electronic address: lenghan@iu.edu.
¹⁶ Department of Molecular and Cellular Oncology, University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA; Graduate School of Biomedical Sciences, University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA. Electronic address: clin2@mdanderson.org.
¹⁷ Department of Molecular and Cellular Oncology, University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA; Center for RNA Interference and Non-Coding RNAs, University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA; Graduate School of Biomedical Sciences, University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA. Electronic address: lyang7@mdanderson.org.

Abstract

Obesity, in which the functional importance of small nucleolar RNAs (snoRNAs) remains elusive, correlates with risk for many cancer types. Here, we identify that the serum copies of adipocyte-expressed SNORD46 correlate with body mass index (BMI), and serum SNORD46 antagonizes interleukin-15 (IL-15) signaling. Mechanically, SNORD46 binds IL-15 via G11, and G11A (a mutation that significantly enhances binding affinity) knockin drives obesity in mice. Functionally, SNORD46 blocks IL-15-induced, FER kinase-dependent phosphorylation of platelet glycoprotein 4 (CD36) and monoglyceride lipase (MGLL) in adipocytes, leading to inhibited lipolysis and browning. In natural killer (NK) cells, SNORD46 suppresses the IL-15-dependent autophagy, leading to reduced viability of obese NK. SNORD46 power inhibitors exhibit anti-obesity effects, concurring with improved viability of obese NK and anti-tumor immunity of CAR-NK cell therapy. Hence, our findings demonstrate the functional importance of snoRNAs in obesity and the utility of snoRNA power inhibitors for antagonizing obesity-associated immune resistance.

Keywords: adipocyte; autophagy; interleukin-15; lipase; natural killer cells; obesity; small nucleolar RNA.

Publication types

Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't
Research Support, U.S. Gov't, Non-P.H.S.

MeSH terms

Adipocytes / metabolism
Animals
Interleukin-15 / metabolism
Killer Cells, Natural
Lipolysis*
Mice
Obesity / metabolism
RNA, Small Nucleolar* / genetics
RNA, Small Nucleolar* / metabolism
Rejuvenation

Substances

RNA, Small Nucleolar
Interleukin-15

Abstract

Publication types

MeSH terms

Substances

Grants and funding