2. Academic Validation
  3. Nuclear envelope budding inhibition slows down progerin-induced aging process

Nuclear envelope budding inhibition slows down progerin-induced aging process

  • Proc Natl Acad Sci U S A. 2024 Oct 8;121(41):e2321378121. doi: 10.1073/pnas.2321378121.
Xiangyang Wang # 1 2,  Lin Ma # 3,  Di Lu 4,  Gan Zhao 1,  He Ren 1,  Qiaoyu Lin 1,  Mingkang Jia 1,  Fan Huang 1,  Shan Wang 3,  Zhe Xu 3,  Zhou Yang 3,  Yan Chu 3,  Zigang Xu 3,  Wei Li 5,  Li Yu 4,  Qing Jiang 1,  Chuanmao Zhang 1 2
Affiliations

Affiliations

  • 1 The Key Laboratory of Cell Proliferation and Differentiation of the Ministry of Education, College of Life Sciences, Peking University, Beijing 100871, China.
  • 2 The Academy for Cell and Life Health, Faculty of Life Science and Technology, Kunming University of Science and Technology, Kunming 650500, China.
  • 3 Department of Dermatology, Beijing Children's Hospital, Capital Medical University, National Center for Children's Health, Beijing 100045, China.
  • 4 The State Key Laboratory of Membrane Biology, Tsinghua University-Peking University Joint Center for Life Sciences, School of Life Sciences, Tsinghua University, Beijing 100084, China.
  • 5 Genetics and Birth Defects Control Center, Beijing Children's Hospital, Capital Medical University, National Center for Children's Health, Beijing 100045, China.
  • # Contributed equally.
PMID: 39352925 DOI: 10.1073/pnas.2321378121
Abstract

Progerin causes Hutchinson-Gilford progeria syndrome (HGPS), but how progerin accelerates aging is still an interesting question. Here, we provide evidence linking nuclear envelope (NE) budding and accelerated aging. Mechanistically, progerin disrupts nuclear lamina to induce NE budding in concert with lamin A/C, resulting in transport of chromatin into the cytoplasm where it is removed via Autophagy, whereas emerin antagonizes this process. Primary cells from both HGPS patients and mouse models express progerin and display NE budding and chromatin loss, and ectopically expressing progerin in cells can mimic this process. More excitingly, we screen a NE budding inhibitor chaetocin by high-throughput screening, which can dramatically sequester progerin from the NE and prevent this NE budding through sustaining ERK1/2 activation. Chaetocin alleviates NE budding-induced chromatin loss and ameliorates HGPS defects in cells and mice and significantly extends lifespan of HGPS mice. Collectively, we propose that progerin-induced NE budding participates in the induction of progeria, highlight the roles of chaetocin and sustained ERK1/2 activation in Anti-aging, and provide a distinct avenue for treating HGPS.

Keywords

ERK1/2; Hutchinson–Gilford progeria syndrome; NE budding; chromatin loss; progerin.

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