Mutant huntingtin alters cell fate in response to microtubule depolymerization via the GEF-H1-RhoA-ERK pathway.
Cellular responses to drug treatment show tremendous variations. Elucidating mechanisms underlying these variations is critical for predicting therapeutic responses and developing personalized therapeutics. Using a small molecule screening approach, we discovered how a disease causing allele leads to opposing cell fates upon pharmacological perturbation. Diverse microtubule-depolymerizing agents protected mutant huntingtin-expressing cells from cell death, while being toxic to cells lacking mutant huntingtin or those expressing wild-type huntingtin. Additional neuronal cell lines and primary neurons from Huntington disease mice also showed altered survival upon microtubule depolymerization. Transcription profiling revealed that microtubule depolymerization induced the autocrine growth factor connective tissue growth factor and activated ERK survival signaling. The genotype-selective rescue was dependent upon increased RhoA protein levels in mutant huntingtin-expressing cells, because inhibition of RhoA, its downstream effector, Rho-associated kinase (ROCK), or a microtubule-associated RhoA activator, guanine nucleotide exchange factor-H1 (GEF-H1), all attenuated the rescue. Conversely, RhoA overexpression in cells lacking mutant huntingtin conferred resistance to microtubule-depolymerizer toxicity. This study elucidates a novel pathway linking microtubule stability to cell survival and provides insight into how genetic context can dramatically alter cellular responses to pharmacological interventions.
Varma
Hemant
H
Department of Biological Sciences, Howard Hughes Medical Institute, New York, New York 10027, USA.
Yamamoto
Ai
A
Sarantos
Melissa R
MR
Hughes
Robert E
RE
Stockwell
Brent R
BR
D000818:Animals; D017209:Apoptosis; D016923:Cell Death; D002460:Cell Line; D002470:Cell Survival; D002478:Cells, Cultured; D048049:Extracellular Signal-Regulated MAP Kinases / Q000235:genetics / Q000378:metabolism; D020662:Guanine Nucleotide Exchange Factors / Q000235:genetics / Q000378:metabolism; D006801:Humans; D000071058:Huntingtin Protein; D006816:Huntington Disease / Q000235:genetics / Q000378:metabolism* / Q000503:physiopathology; D051379:Mice; D008870:Microtubules / Q000235:genetics / Q000378:metabolism*; D009154:Mutation; D009419:Nerve Tissue Proteins / Q000235:genetics* / Q000378:metabolism; D009474:Neurons / Q000166:cytology / Q000378:metabolism*; D009687:Nuclear Proteins / Q000235:genetics* / Q000378:metabolism; D051381:Rats; D015398:Signal Transduction; D020742:rhoA GTP-Binding Protein / Q000235:genetics / Q000378:metabolism
D020662:Guanine Nucleotide Exchange Factors; C086055:HTT protein, human; D000071058:Huntingtin Protein; D009419:Nerve Tissue Proteins; D009687:Nuclear Proteins; D048049:Extracellular Signal-Regulated MAP Kinases; D020742:rhoA GTP-Binding Protein