Association of CHMP4B and autophagy with micronuclei: implications for cataract formation.

Antonia P Sagona,Ioannis P Nezis,Harald Stenmark

doi:10.1155/2014/974393

Abstract

Autophagy is a mechanism of cellular self-degradation that is very important for cellular homeostasis and differentiation. Components of the endosomal sorting complex required for transport (ESCRT) machinery are required for endosomal sorting and also for autophagy and the completion of cytokinesis. Here we show that the ESCRT-III subunit CHMP4B not only localizes to normal cytokinetic bridges but also to chromosome bridges and micronuclei, the latter surrounded by lysosomes and autophagosomes. Moreover, CHMP4B can be co-immunoprecipitated with chromatin. Interestingly, a CHMP4B mutation associated with autosomal dominant posterior polar cataract abolishes the ability of CHMP4B to localize to micronuclei. We propose that CHMP4B, through its association with chromatin, may participate in the autophagolysosomal degradation of micronuclei and other extranuclear chromatin. This may have implications for DNA degradation during lens cell differentiation, thus potentially protecting lens cells from cataract development.

Highlights

Autophagy is an evolutionarily conserved process where the cells degrade their own cellular material
The endosomal sorting complex required for transport (ESCRT) machinery is required for multivesicular body (MVB) biogenesis, budding of HIV-1 and other enveloped viruses, macroautophagy, and cytokinesis [3, 4]
Previous studies have shown that CHMP4B localizes to the intercellular bridge adjacent to the midbody during cytokinesis in HeLa cells [7, 8, 17]

Summary

Introduction

Autophagy is an evolutionarily conserved process where the cells degrade their own cellular material. It is involved in protein and organelle degradation and plays an essential role in cellular and whole-animal homeostasis and differentiation. During autophagy there is sequestration of cellular material into double-membrane vesicles called autophagosomes. The autophagosomes fuse with endocytic vesicles to form the amphisomes, which contain both endocytic and autophagic cargo. The autophagosomes and/or amphisomes are subsequently fused with the lysosomes where the sequestered cargoes are degraded by lysosomal hydrolases. Autophagy serves as a cellular response in nutrient starvation but is responsible for the removal of aggregated proteins and damaged organelles and plays an important role in the quality control of proteins and organelles. Dysfunctional autophagy is implicated in ageing, neurodegeneration, infections, tumorigenesis, heart disease, liver and lung disease, myopathies, and cataract formation [2] and it is important to characterize this process at the molecular level

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