ESCRTing autophagic clearance of aggregating proteins

Abstract

Autophagy has recently been found to play an important role in the degradation of damaged macromolecules, in particular misfolded, aberrant proteins that can disrupt neuronal function and cause neurodegeneration if not removed. Mutations in the Endosomal Sorting Complex Required for Transport (ESCRT)-III subunit CHMP2B were recently associated with frontotemporal dementia (FTD) and amyotrophic lateral sclerosis (ALS), neurodegenerative diseases characterized by abnormal ubiquitin-positive protein deposits in affected neurons. The ESCRT proteins are known to sort ubiquitinated integral membrane proteins into intralumenal vesicles of the multivesicular body (MVB), but it was not known how ESCRT mutations could cause neurodegenerative disease. We found autophagic degradation to be inhibited in cells depleted of ESCRT subunits or expressing CHMP2B mutants and in Drosphila melanogaster lacking ESCRTs. In addition to accumulation of autophagic vesicles, we also found increased levels of membrane-free ubiquitin-positive protein aggregates in ESCRT-depleted cells. Using cellular and Drosophila models for Huntington’s disease, we showed that reduced ESCRT levels inhibit clearance of expanded polyglutamine aggregates and aggravate their neurotoxic effect. Together, our data indicate that efficient autophagic degradation requires functional MVBs and provide a possible explanation to the observed neurodegenerative phenotype seen in patients with CHMP2B mutations. In this addendum we discuss models to explain the functions of ESCRTs and MVBs in autophagic degradation.Addendum to: Filimonenko M, Stuffers S, Raiborg C, Yamamoto A, Malerod L, Fisher EM, Isaacs A, Brech A, Stenmark H, Simonsen A. Functional multivesicular bodies are required for autophagic clearance of protein aggregates associated with neurodegenerative disease. J Cell Biol 2007; 179;485-500.andRusten TE, Vaccari T, Lindmo K, Rodahl LM, Nezis IP, Sem-Jacobsen C, Wendler F, Vincent JP, Brech A, Bilder D, Stenmark H. ESCRTs and Fab1 regulate distinct steps of autophagy. Curr Biol 2007; 17;1817-25.