Molecular Mechanisms of snoRNA-IL-15 Crosstalk in Adipocyte Lipolysis and NK Cell Rejuvenation

Authors

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

Publication Date

8-8-2023

Journal

Cell Metabolism

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

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

Comments

Supplementary Materials

PMID: 37329887