Editors' ChoiceCell Biology

Huntingtin Adapts to Autophagy

See allHide authors and affiliations

Sci. Signal.  02 Dec 2014:
Vol. 7, Issue 354, pp. ec334
DOI: 10.1126/scisignal.aaa3739

Huntington’s disease is a neurodegenerative disorder caused by a CAG trinucleotide-repeat expansion in the gene Huntingtin (HTT). The CAG-expansion encodes an expanded polyglutamine tract in HTT protein that leads to protein accumulation and aggregation, cellular stress, and subsequent neuronal toxicity. Autophagy is an adaptive process by which cells recycle proteins and organelles during periods of nutrient deprivation and respond to cellular stress. Wild-type HTT protein has no reported molecular function but shares sequence homology with three different yeast proteins involved in autophagy (Atg11, Atg23, and Vac8). Atg11 is an adaptor protein that interacts with Atg23, Vac8, and several other autophagy-associated proteins. Ochaba et al. found that a null mutation in HTT reduced the molecular and behavioral responses associated with starvation-induced autophagy in Drosophila melanogaster larvae. Moreover, conditional knockout of Htt in the mouse forebrain caused progressive accumulation of ubiquitin, lipofuscin (a lipid pigment associated with lysosomal degradation), and p62 (a substrate adaptor for selective autophagy), consistent with inhibition of autophagy. In cultured human cells, the C-terminus of human HTT interacted with the N-terminus of HTT, as well as with p62, other adaptors for selective autophagy, and several other proteins involved in the autophagy cascade. Thus, HTT may function similar to yeast Atg11 as a scaffold for multiple autophagy-associated proteins, and thereby promote selective autophagy of multiple substrates.

J. Ochaba, T. Lukacsovich, G. Csikos, S. Zheng, J. Margulis, L. Salazar, K. Mao, A. L. Lau, S. Y. Yeung, S. Humbert, F. Saudou, D. J. Klionsky, S. Finkbeiner, S. O. Zeitlin, J. L. Marsh, D. E. Housman, L. M. Thompson, J. S. Steffan, Potential function for the Huntingtin protein as a scaffold for selective autophagy. Proc. Natl. Acad. Sci. U.S.A. 111, 16889–16894 (2014). [Abstract] [Full Text]