The COOH-terminal domain of huntingtin interacts with RhoGEF kalirin and modulates cell survival

Sci Rep. 2018 May 22;8(1):8000. doi: 10.1038/s41598-018-26255-1.

Abstract

Human huntingtin (Htt) contains 3144 amino acids and has an expanded polyglutamine region near the NH2-terminus in patients with Huntington's disease. While numerous binding partners have been identified to NH2-terminal Htt, fewer proteins are known to interact with C-terminal domains of Htt. Here we report that kalirin, a Rac1 activator, is a binding partner to C-terminal Htt. Kalirin and Htt co-precipitated from mouse brain endosomes and co-localized at puncta in NRK and immortalized striatal cells and primary cortical neurons. We mapped the interaction domains to kalirin674-1272 and Htt2568-3144 and determined that the interaction between kalirin and Htt was independent of HAP1, a known interactor for Htt and kalirin. Kalirin precipitated with mutant Htt was more abundant than with wild-type Htt and had a reduced capacity to activate Rac1 when mutant Htt was present. Expression of Htt2568-3144 caused cytotoxicity, partially rescued by co-expressing kalirin674-1272 but not other regions of kalirin. Our study suggests that the interaction of kalirin with the C-terminal region of Htt influences the function of kalirin and modulates the cytotoxicity induced by C-terminal Htt.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Cell Survival / genetics
  • Cells, Cultured
  • Guanine Nucleotide Exchange Factors / metabolism*
  • Humans
  • Huntingtin Protein / chemistry*
  • Huntingtin Protein / genetics
  • Huntingtin Protein / metabolism*
  • MCF-7 Cells
  • Mice
  • Mice, Transgenic
  • Protein Binding / physiology
  • Protein Interaction Domains and Motifs* / genetics
  • Protein-Serine-Threonine Kinases / metabolism*
  • Rho Guanine Nucleotide Exchange Factors / metabolism

Substances

  • Guanine Nucleotide Exchange Factors
  • HTT protein, human
  • Htt protein, mouse
  • Huntingtin Protein
  • Rho Guanine Nucleotide Exchange Factors
  • kalirin protein, mouse
  • KALRN protein, human
  • Protein-Serine-Threonine Kinases