김성준 (Mayo Clinic) | 한빛사논문 > 한빛사

한빛사논문

조회109

Mayo Clinic

CV File

Nat. Immunol., Published: 29 January 2026 | https://doi.org/10.1038/s41590-025-02377-3 SIRT2-mediated deacetylation of LCK governs the magnitude of T cell receptor signaling

Imene Hamaidi^1,2,17, Pingyan Cheng^1,2,3,17, Soo Young Jun^1,4, Alak Manna^1,2, Min-Hsuan Wang⁵, Anh Nguyen^1,2,4, Ismail Can ⁶, Min G. Zhang⁷, Odesha O. Taylor⁷, Luis Uriel Lopez Bailon⁸, Bin Fang ⁹, Bradford Perez¹⁰, Ben C. Creelan¹¹, Andriy Marusyk¹², Dongjun Shin¹³, Tae Hyun Hwang¹⁴, Anders E. Berglund¹⁵, Virginia S. Shapiro¹⁶, Haitao M. Ji⁷, José R. Conejo-Garcia⁸ & Sungjune Kim^1,2,4

¹Department of Cancer Biology, Mayo Clinic, Jacksonville, FL, USA.
²Department of Immunology, Mayo Clinic, Jacksonville, FL, USA.
³TuHURA Biosciences Inc., Tampa, FL, USA.
⁴Department of Radiation Oncology, Mayo Clinic, Jacksonville, FL, USA.
⁵Taipei Veterans Generation Hospital, Taipei, Taiwan.
⁶Division of Hematology, Mayo Clinic, Rochester, MN, USA.
⁷Department of Drug Discovery, H. Lee Moffitt Cancer Center, Tampa, FL, USA.
⁸Department of Integrative Immunobiology, Duke School of Medicine, Durham, NC, USA.
⁹Proteomics Core, H. Lee Moffitt Cancer Center, Tampa, FL, USA.
¹⁰Florida Cancer Specialists & Research Institute, Trinity Cancer Center, Trinity, FL, USA.
¹¹Thoracic Oncology Program, H. Lee Moffitt Cancer Center, Tampa, FL, USA.
¹²Department of Tumor Biology, H. Lee Moffitt Cancer Center, Tampa, FL, USA.
¹³Tomocube Inc., San Diego, CA, USA.
¹⁴AI Research in Section of Surgical Sciences, Vanderbilt University, Nashville, TN, USA.
¹⁵Department of Quantitative Health Sciences, Mayo Clinic, Jacksonville, FL, USA.
¹⁶Department of Immunology, Mayo Clinic, Rochester, MN, USA.
¹⁷These authors contributed equally: Imene Hamaidi, Pingyan Cheng.

Corresponding author
Correspondence to Sungjune Kim.

Abstract

T cell receptor (TCR) signaling is precisely tuned to prevent self-reactivity while allowing protective immunity. Here we found that acetylation modulated TCR signaling. The loss of SIRT2 deacetylase activity in T cells led to amplified calcium mobilization and phosphorylation of key proximal TCR molecules in naive T cells and reversed dampened TCR signaling in anergic T cells. During thymic selection, SIRT2 deficiency lowered the TCR signaling threshold and resulted in a broader TCR repertoire diversity. Mechanistically, we identified acetyl-lysine K228 on the linker region of LCK as a substrate specific for SIRT2 that governed LCK conformation and activity. SIRT2 inhibition in exhausted mouse and human tumor-infiltrating T cells restored TCR responsiveness and antitumor immunity. These findings highlighted SIRT2-modulated protein acetylation as a regulatory mechanism that set the TCR threshold in T cells.

논문정보