Molecular mechanisms of snoRNA-IL15 crosstalk in adipocyte lipolysis and NK cell rejuvenation

Obesity, in which the functional importance of small nucleolar RNAs (snoRNAs) remains elusive, correlates with the risk for many cancer types. Here, we identify that the serum copies of adipocyte-expressed SNORD46 correlates with body mass index (BMI) and serum SNORD46 antagonizes interleukin-15 (IL15) signaling. Mechanically, SNORD46 binds IL15 via G11 and G11A (a mutation significantly enhances binding affinity) knockin drives obesity in mice. Functionally, SNORD46 blocks IL15-induced, FER kinase-dependent phosphorylation of platelet glycoprotein 4 (CD36) and monoglyceride lipase (MGLL) in adipocytes, leading to inhibited lipolysis and browning. In nature killer (NK) cells, SNORD46 suppresses the IL15-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.