美国德克萨斯大学MD安德森癌症中心Liuqing Yang，Chunru Lin，美国德州农工大学生物科学与技术研究所Leng Han和美国贝勒医学院Zhi Tan共同合作，近期取得重要工作进展。他们研究发现了脂肪细胞脂解和NK细胞再生中snoRNA与IL-15的分子交互机制。相关研究成果2023年6月16日在线发表于《细胞—代谢》杂志上。

据介绍，肥胖与许多癌症类型的风险相关，其中核仁小RNA（snoRNA）的功能重要性仍不明确。

研究人员发现，脂肪细胞表达的SNORD46的血清拷贝与体重指数（BMI）相关，并且血清SNORD46拮抗白细胞介素-15（IL-15）信号传导。从机制上讲，SNORD46通过G11与IL-15结合，而G11A（一种显著增强结合亲和力的突变）敲除会导致小鼠肥胖。在功能上，SNORD46阻断IL-15诱导的脂肪细胞中血小板糖蛋白4（CD36）和单甘油酯脂肪酶（MGLL）的FER激酶依赖性磷酸化，从而抑制脂解和褐变。在自然杀伤细胞（NK）中，SNORD46抑制IL-15依赖性自噬，导致肥胖NK的生存能力降低。SNORD46强效抑制剂具有抗肥胖作用，同时提高了肥胖NK的生存能力和CAR-NK细胞治疗的抗肿瘤免疫力。

因此，这一研究结果证明了snoRNA在肥胖中的功能重要性，以及snoRNA强效抑制剂在对抗肥胖相关免疫抵抗方面的效用。

附：英文原文 

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

Author: 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

Issue&Volume: 2023-06-16

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.

DOI: 10.1016/j.cmet.2023.05.009

Source: https://www.cell.com/cell-metabolism/fulltext/S1550-4131(23)00186-9