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

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 YuMien Chie Hung, Michael A. Curran, Katayoun Rezvani, Boyi Gan, Zhi Tan, Leng Han, Chunru Lin, Liuqing Yang

Research output: Contribution to journal › Article › peer-review

10 Scopus citations

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.

Original language	English (US)
Pages (from-to)	1457-1473.e13
Journal	Cell Metabolism
Volume	35
Issue number	8
DOIs	https://doi.org/10.1016/j.cmet.2023.05.009
State	Published - Aug 8 2023

Keywords

adipocyte
autophagy
interleukin-15
lipase
natural killer cells
obesity
small nucleolar RNA

ASJC Scopus subject areas

Physiology
Molecular Biology
Cell Biology

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10.1016/j.cmet.2023.05.009

Cite this

Zhang, Y., Zhao, Z., Huang, L. A., Liu, Y., Yao, J., Sun, C., Li, Y., Zhang, Z., Ye, Y., Yuan, F., Nguyen, T. K., Garlapati, N. R., Wu, A., Egranov, S. D., Caudle, A. S., Sahin, A. A., Lim, B., Beretta, L., Calin, G. A., ... Yang, L. (2023). Molecular mechanisms of snoRNA-IL-15 crosstalk in adipocyte lipolysis and NK cell rejuvenation. Cell Metabolism, 35(8), 1457-1473.e13. https://doi.org/10.1016/j.cmet.2023.05.009

Zhang, Y, Zhao, Z, Huang, LA, Liu, Y, Yao, J, Sun, C, Li, Y, Zhang, Z, Ye, Y, Yuan, F, Nguyen, TK, Garlapati, NR, Wu, A, Egranov, SD, Caudle, AS , Sahin, AA , Lim, B , Beretta, L , Calin, GA , Yu, D, Hung, MC, Curran, MA , Rezvani, K , Gan, B, Tan, Z, Han, L, Lin, C & Yang, L 2023, 'Molecular mechanisms of snoRNA-IL-15 crosstalk in adipocyte lipolysis and NK cell rejuvenation', Cell Metabolism, vol. 35, no. 8, pp. 1457-1473.e13. https://doi.org/10.1016/j.cmet.2023.05.009

@article{798a03b8128243bf9f648f45d8e1987e,

title = "Molecular mechanisms of snoRNA-IL-15 crosstalk in adipocyte lipolysis and NK cell rejuvenation",

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",

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

note = "Publisher Copyright: {\textcopyright} 2023 The Authors",

year = "2023",

month = aug,

day = "8",

doi = "10.1016/j.cmet.2023.05.009",

language = "English (US)",

volume = "35",

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TY - JOUR

T1 - Molecular mechanisms of snoRNA-IL-15 crosstalk in adipocyte lipolysis and NK cell rejuvenation

AU - Zhang, Yaohua

AU - Zhao, Zilong

AU - Huang, Lisa A.

AU - Liu, Yuan

AU - Yao, Jun

AU - Sun, Chengcao

AU - Li, Yajuan

AU - Zhang, Zhao

AU - Ye, Youqiong

AU - Yuan, Fei

AU - Nguyen, Tina K.

AU - Garlapati, Nikhil Reddy

AU - Wu, Andrew

AU - Egranov, Sergey D.

AU - Caudle, Abigail S.

AU - Sahin, Aysegul A.

AU - Lim, Bora

AU - Beretta, Laura

AU - Calin, George A.

AU - Yu, Dihua

AU - Hung, Mien Chie

AU - Curran, Michael A.

AU - Rezvani, Katayoun

AU - Gan, Boyi

AU - Tan, Zhi

AU - Han, Leng

AU - Lin, Chunru

AU - Yang, Liuqing

PY - 2023/8/8

Y1 - 2023/8/8

N2 - 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.

AB - 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.

KW - adipocyte

KW - autophagy

KW - interleukin-15

KW - lipase

KW - natural killer cells

KW - obesity

KW - small nucleolar RNA

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U2 - 10.1016/j.cmet.2023.05.009

DO - 10.1016/j.cmet.2023.05.009

M3 - Article

C2 - 37329887

AN - SCOPUS:85166555993

SN - 1550-4131

VL - 35

SP - 1457-1473.e13

JO - Cell Metabolism

JF - Cell Metabolism

IS - 8

ER -

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

Abstract

Keywords

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