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Nat. Commun., 17 February 2025 | https://doi.org/10.1038/s41467-025-56929-0
Cell enlargement modulated by GATA4 and YAP instructs the senescence-associated secretory phenotype
Joae Joung1,2, Yekang Heo1,2,5, Yeonju Kim1,2,5, Jaejin Kim1,2,5, Haebeen Choi1,2, Taerang Jeon1,2, Yeji Jang1,2, Eun-Jung Kim1,2, Sang Heon Lee3, Jae Myoung Suh3, Stephen J. Elledge4, Mi-Sung Kim1,2 &Chanhee Kang1,2
1School of Biological Sciences, Seoul National University, Seoul 08826, South Korea.
2Center for Systems Geroscience, Seoul National University, Seoul 08826, South Korea.
3Graduate School of Medical Science and Engineering, KAIST, Daejeon 34141, South Korea.
4Department of Genetics, Harvard Medical School and Division of Genetics, Brigham and Women’s Hospital, Howard Hughes Medical Institute, Boston, MA 02115, USA.
5These authors contributed equally: Yekang Heo, Yeonju Kim, Jaejin Kim.
Corresponding authors
Correspondence to Mi-Sung Kim or Chanhee Kang.
1School of Biological Sciences, Seoul National University, Seoul 08826, South Korea.
2Center for Systems Geroscience, Seoul National University, Seoul 08826, South Korea.
3Graduate School of Medical Science and Engineering, KAIST, Daejeon 34141, South Korea.
4Department of Genetics, Harvard Medical School and Division of Genetics, Brigham and Women’s Hospital, Howard Hughes Medical Institute, Boston, MA 02115, USA.
5These authors contributed equally: Yekang Heo, Yeonju Kim, Jaejin Kim.
Corresponding authors
Correspondence to Mi-Sung Kim or Chanhee Kang.
Abstract
Dynamic changes in cell size are associated with development and pathological conditions, including aging. Although cell enlargement is a prominent morphological feature of cellular senescence, its functional implications are unknown; moreover, how senescent cells maintain their enlargement state is less understood. Here we show that an extensive remodeling of actin cytoskeleton is necessary for establishing senescence-associated cell enlargement and pro-inflammatory senescence-associated secretory phenotype (SASP). This remodeling is attributed to a balancing act between the SASP regulator GATA4 and the mechanosensor YAP on the expression of the Rho family of GTPase RHOU. Genetic or pharmacological interventions that reduce cell enlargement attenuate SASP with minimal effect on senescence growth arrest. Mechanistically, actin cytoskeleton remodeling couples cell enlargement to the nuclear localization of GATA4 and NF-κB via the Linker of Nucleoskeleton and Cytoskeleton (LINC) complex. RhoU protein accumulates in mouse adipose tissue under senescence-inducing conditions. Furthermore, RHOU expression correlates with SASP expression in adipose tissue during human aging. Thus, our study highlights an unexpected instructive role of cell enlargement in modulating the SASP and reveals a mechanical branch in the senescence regulatory network.
논문정보
- Research article
- 2025년 02월 (BRIC 등록일 2025-02-19)
- 국내(교신)+국외 연구진
- 생명과학 > 노화/암생물학
관련 보도자료
오랜 미스터리였던 좀비 세포 거대화의 비밀, 노화연관 염증 반응의 새로운 조절 기전 제시!
강찬희 교수는“본 연구는 오랜 기간 동안 미스터리로 남아 있던 노화 세포의 비대증 조절 및 작용 기전을 최초로 규명하였다는 점에서 큰 과학적 의의가 있다”고 밝혔다. 연구의 공동 교신 저자인 김미성 연구교수(시스템스 노화기전 연구센터, 센터장: 정종경 교수)는“노화 비대증 제어를 통해 노화연관 염증 반응을 억제할 수 있다는 점에서 신규 노화 치료 전략을 제시한 연구”라며“해당 제어법은 노화의 기본 단위인 세포 노화를 표적으로 삼기에, 대사 질환뿐만 아니라 다양한 노화연관 질환에도 적용 가능성이 크다”라고 말했다.
- Bio통신원
- 2025. 03. 14
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