ESCRT-III controls nuclear envelope deformation induced by progerin

Sci Rep. 2020 Nov 2;10(1):18877. doi: 10.1038/s41598-020-75852-6.


Hutchinson-Gilford progeria syndrome (HGPS) is a premature aging disorder, caused by mutation in the gene encoding lamin A/C, which produces a truncated protein called progerin. In cells from HGPS patients, progerin accumulates at the nuclear membrane (NM), where it causes NM deformations. In this study, we investigated whether progerin-induced NM deformation involved ESCRT-III, a protein complex that remodels nuclear and cytoplasmic membranes. The ESCRT-III protein CHMP4B was recruited to sites of aberrant NM proliferation in human cells ectopically expressing progerin and in patient-derived HGPS fibroblasts. Derepression of NM deformation in these cells was observed following depletion of CHMP4B or an ESCRT-III adaptor, ALIX. Treatment with rapamycin (which induce autophagic clearance of progerin and reverse progerin-induced cellular phenotypes) down-regulated progerin-induced NM deformation, whereas treatment with bafilomycin A1 (an inhibitor of autophagy and lysosome-based degradation) or CHMP4B depletion antagonized the effects of rapamycin. These results indicate that the ALIX-mediated ESCRT-III pathway plays a suppressive role in progerin-induced NM deformation and suggest that autophagy down-regulates progerin-induced NM deformation in a manner dependent on ESCRT-III machinery.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Aging / drug effects
  • Aging / genetics
  • Calcium-Binding Proteins / genetics*
  • Calcium-Binding Proteins / metabolism
  • Cell Cycle Proteins / genetics*
  • Cell Cycle Proteins / metabolism
  • Cell Line
  • Cell Nucleus / drug effects
  • Cell Proliferation / drug effects
  • Endosomal Sorting Complexes Required for Transport / antagonists & inhibitors
  • Endosomal Sorting Complexes Required for Transport / genetics*
  • Endosomal Sorting Complexes Required for Transport / metabolism
  • Fibroblasts / drug effects
  • Humans
  • Lamin Type A / genetics*
  • Lamin Type A / metabolism
  • Macrolides / pharmacology
  • Mutation / genetics
  • Nuclear Envelope / metabolism
  • Nuclear Envelope / pathology
  • Progeria / genetics*
  • Progeria / metabolism
  • Progeria / pathology
  • Sirolimus / pharmacology


  • CHMP4B protein, human
  • Calcium-Binding Proteins
  • Cell Cycle Proteins
  • Endosomal Sorting Complexes Required for Transport
  • Lamin Type A
  • Macrolides
  • PDCD6IP protein, human
  • prelamin A
  • bafilomycin A1
  • Sirolimus