ESCRT-III controls nuclear envelope deformation induced by progerin.

Area of Science:

• Cell Biology
• Molecular Biology
• Genetics

Background:

• Hutchinson-Gilford progeria syndrome (HGPS) is a rare genetic disorder characterized by premature aging.
• It stems from mutations in the lamin A/C gene, leading to the production of a toxic protein called progerin.
• Progerin accumulation at the nuclear membrane causes significant cellular abnormalities, including nuclear envelope deformations.

Purpose of the Study:

• To investigate the role of the ESCRT-III complex in progerin-induced nuclear membrane (NM) deformation.
• To explore the interplay between progerin, ESCRT-III, and autophagy in HGPS cellular phenotypes.

Main Methods:

• Studied human cells ectopically expressing progerin and patient-derived HGPS fibroblasts.
• Utilized techniques such as protein depletion (CHMP4B, ALIX) and pharmacological treatments (rapamycin, bafilomycin A1).
• Observed recruitment of ESCRT-III components and assessed NM deformation and progerin clearance.

Main Results:

• The ESCRT-III protein CHMP4B was recruited to sites of nuclear membrane abnormalities in HGPS models.
• Depletion of CHMP4B or its adaptor ALIX led to increased NM deformation.
• Rapamycin treatment reduced NM deformation by promoting progerin clearance, an effect dependent on ESCRT-III and autophagy.

Conclusions:

• The ALIX-mediated ESCRT-III pathway plays a crucial suppressive role in progerin-induced nuclear membrane deformation.
• Autophagy effectively down-regulates progerin-induced NM deformation, with its efficacy dependent on the ESCRT-III machinery.