Details

Autor(en) / Beteiligte

• O’Rourke, Jacqueline Gire
• Gareau, Jaclyn R.
• Ochaba, Joseph
• Song, Wan
• Raskó, Tamás
• Reverter, David
• Lee, John
• Monteys, Alex Mas
• Pallos, Judit
• Mee, Lisa
• Vashishtha, Malini
• Apostol, Barbara L.
• Nicholson, Thomas Peter
• Illes, Katalin
• Zhu, Ya-Zhen
• Dasso, Mary
• Bates, Gillian P.
• Difiglia, Marian
• Davidson, Beverly
• Wanker, Erich E.
• Marsh, J. Lawrence
• Lima, Christopher D.
• Steffan, Joan S.
• Thompson, Leslie M.

Titel

SUMO-2 and PIAS1 Modulate Insoluble Mutant Huntingtin Protein Accumulation

Ist Teil von

• Cell reports (Cambridge), 2013-07, Vol.4 (2), p.362-375

Ort / Verlag

United States: Elsevier Inc

Erscheinungsjahr

2013

Quelle

Free E-Journal (出版社公開部分のみ）

Beschreibungen/Notizen

• A key feature in Huntington disease (HD) is the accumulation of mutant Huntingtin (HTT) protein, which may be regulated by posttranslational modifications. Here, we define the primary sites of SUMO modification in the amino-terminal domain of HTT, show modification downstream of this domain, and demonstrate that HTT is modified by the stress-inducible SUMO-2. A systematic study of E3 SUMO ligases demonstrates that PIAS1 is an E3 SUMO ligase for both HTT SUMO-1 and SUMO-2 modification and that reduction of dPIAS in a mutant HTT Drosophila model is protective. SUMO-2 modification regulates accumulation of insoluble HTT in HeLa cells in a manner that mimics proteasome inhibition and can be modulated by overexpression and acute knockdown of PIAS1. Finally, the accumulation of SUMO-2-modified proteins in the insoluble fraction of HD postmortem striata implicates SUMO-2 modification in the age-related pathogenic accumulation of mutant HTT and other cellular proteins that occurs during HD progression. [Display omitted] •SUMO-modifying enzymes are expressed in mouse brain•HTT is modified by SUMO-2, and PIAS1 enhances SUMO-2 modification•Reduction of dPIAS is neuroprotective in flies•SUMO-2-modified protein accumulates in human HD striata The accumulation of mutant Huntingtin (HTT) is a key feature in Huntington disease (HD). Here, Thompson and colleagues describe the relationship between posttranslational modification of mutant HTT by SUMO-2 and the accumulation of high molecular weight, insoluble protein. SUMO-2-modified proteins dramatically accumulate in human HD brain. Furthermore, PIAS1 is demonstrated to function as an E3-SUMO ligase for HTT that can regulate the SUMO modification and accumulation of mutant HTT. These results have important implications for the treatment of HD and other neurodegenerative diseases.