The Role of Sgt1 in Methamphetamine/Hyperthermia-induced Necroptosis

Introduction: Methamphetamine (METH) is a synthetic drug widely abused globally and can result in hyperthermia (HT) and psychiatric symptoms. Our previous studies showed that heat shock protein 90 alpha (HSP90α) plays a vital role in METH/HT-elicited neuronal necroptosis; however, the detailed mechanism of HSP90α regulation remained obscure. Methods: Herein, we demonstrated a function of the suppressor of G-two allele of SKP1 (Sgt1) in METH/HT-induced necroptosis. Sgt1 was mainly expressed in neurons, co-located with HSP90α, and increased in rat striatum after METH treatment. METH/HT injury triggered necroptosis and increased Sgt1 expression in PC-12 cells. Results: Data from computer simulations indicated that Sgt1 might interact with HSP90α. Geldanamycin (GA), the specific inhibitor of HSP90α, attenuated the interaction between Sgt1 and HSP90α. Knockdown of Sgt1 expression did not affect the expression level of HSP90α. Still, it inhibited the expression of receptor-interacting protein 3 (RIP3), mixed lineage kinase domain-like protein (MLKL), p-RIP3, and p-MLKL, as well as necroptosis induced by METH/HT injury. Conclusion: In conclusion, Sgt1 may regulate the expression of RIP3, p-RIP3, MLKL, and p-MLKL by assisting HSP90α in affecting the METH/HT-induced necroptotic cell death.