McClory, HollisWang, XiaolongSapp, EllenGatune, Leah W.Iuliano, MariaWu, Chiu-YiNathwani, GinaKegel-Gleason, Kimberly B.DiFiglia, MarianLi, Xueyi2018-06-272018McClory, Hollis, Xiaolong Wang, Ellen Sapp, Leah W. Gatune, Maria Iuliano, Chiu-Yi Wu, Gina Nathwani, Kimberly B. Kegel-Gleason, Marian DiFiglia, and Xueyi Li. 2018. “The COOH-terminal domain of huntingtin interacts with RhoGEF kalirin and modulates cell survival.” Scientific Reports 8 (1): 8000. doi:10.1038/s41598-018-26255-1. http://dx.doi.org/10.1038/s41598-018-26255-1.http://nrs.harvard.edu/urn-3:HUL.InstRepos:37160098Human 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.en-USJournal Article2018-06-2710.1038/s41598-018-26255-1