ikkα and ikkβ regulation of dna damage-induced cleavage of huntingtinikkα和ikkβ监管杭丁顿蛋白的dna损害乳沟.pdfVIP

IKKa and IKKb Regulation of DNA Damage-Induced Cleavage of Huntingtin 1 1 1 2 1 Ali Khoshnan *, Jan Ko , Simona Tescu , Patrick Brundin , Paul H. Patterson 1 Biology Division 216-76, California Institute of Technology, Pasadena, California, United States of America, 2 Neuronal Survival Unit, Department of Experimental Medical Science, Wallenberg Neuroscience Center, Lund, Sweden Abstract Background: Proteolysis of huntingtin (Htt) plays a key role in the pathogenesis of Huntington’s disease (HD). However, the environmental cues and signaling pathways that regulate Htt proteolysis are poorly understood. One stimulus may be the DNA damage that accumulates in neurons over time, and the subsequent activation of signaling pathways such as those regulated by IkB kinase (IKK), which can influence neurodegeneration in HD. Methodology/Principal Findings: We asked whether DNA damage induces the proteolysis of Htt and if activation of IKK plays a role. We report that treatment of neurons with the DNA damaging agent etoposide or c-irradiation promotes cleavage of wild type (WT) and mutant Htt, generating N-terminal fragments of 80–90 kDa. This event requires IKKb and is suppressed by IKKa. Elevated levels of IKKa, or inhibition of IKKb expression by a specific small hairpin RNA (shRNA) or its activity by sodium salicylate, prevents Htt proteolysis and increases neuronal resistance to DNA damage. Moreover, IKKb phosphorylates the anti-apoptotic protein Bcl-xL, a modification known to reduce Bcl-xL levels, and activates caspases that can cleave Htt. When IKKb expression is blocked, etoposide treatment does not decrease Bcl-xL and activation of caspases is diminished. Similar to silencing of IKKb, increasing the level of Bcl-xL in neurons prevents etoposi