Cell enlargement modulated by GATA4 and YAP instructs the senescence-associated secretory phenotype

Joae Joung, Yekang Heo, Yeonju Kim, Jaejin Kim, Haebeen Choi, Taerang Jeon, Yeji Jang, Eun-Jung Kim, Sang Heon Lee, Jae Myoung Suh, Stephen J. Elledge, Mi-Sung Kim () and Chanhee Kang ()
Additional contact information
Joae Joung: Seoul National University
Yekang Heo: Seoul National University
Yeonju Kim: Seoul National University
Jaejin Kim: Seoul National University
Haebeen Choi: Seoul National University
Taerang Jeon: Seoul National University
Yeji Jang: Seoul National University
Eun-Jung Kim: Seoul National University
Sang Heon Lee: KAIST
Jae Myoung Suh: KAIST
Stephen J. Elledge: Howard Hughes Medical Institute
Mi-Sung Kim: Seoul National University
Chanhee Kang: Seoul National University

Nature Communications, 2025, vol. 16, issue 1, 1-19

Abstract: 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.

Date: 2025
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DOI: 10.1038/s41467-025-56929-0

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