title: Heat shock protein 70.1 (Hsp70.1) affects neuronal cell fate by regulating lysosomal acid sphingomyelinase.
abstract: The inducible expression of heat shock protein 70.1 (Hsp70.1) plays cytoprotective roles in its molecular chaperone function. Binding of Hsp70 to an endolysosomal phospholipid, bis(monoacylglycero)phosphate (BMP), has been recently shown to stabilize lysosomal membranes by enhancing acid sphingomyelinase (ASM) activity in cancer cells. Using the monkey experimental paradigm, we have reported that calpain-mediated cleavage of oxidized Hsp70.1 causes neurodegeneration in the hippocampal cornu ammonis 1 (CA1), whereas expression of Hsp70.1 in the motor cortex without calpain activation contributes to neuroprotection. However, the molecular mechanisms of the lysosomal destabilization/stabilization determining neuronal cell fate have not been elucidated. To elucidate whether regulation of lysosomal ASM could affect the neuronal fate, we analyzed Hsp70.1-BMP binding and ASM activity by comparing the motor cortex and the CA1. We show that Hsp70.1 being localized at the lysosomal membrane, lysosomal lipid BMP levels, and the lipid binding domain of Hsp70.1 are crucial for Hsp70.1-BMP binding. In the postischemic motor cortex, Hsp70.1 being localized at the lysosomal membrane could bind to BMP without calpain activation and decreased BMP levels, resulting in increasing ASM activity and lysosomal stability. However, in the postischemic CA1, calpain activation and a concomitant decrease in the lysosomal membrane localization of Hsp70.1 and BMP levels may diminish Hsp70.1-BMP binding, resulting in decreased ASM activity and lysosomal rupture with leakage of cathepsin B into the cytosol. A TUNEL assay revealed the differential neuronal vulnerability between the CA1 and the motor cortex. These results suggest that regulation of ASM activation in vivo by Hsp70.1-BMP affects lysosomal stability and neuronal survival or death after ischemia/reperfusion.
authors: From the Departments of Restorative Neurosurgery, Molecular Pharmacology, and.
authors: Hong
authors: H
authors: Zhu
authors: Molecular Pharmacology, and.
authors: Tanihiro
authors: T
authors: Yoshimoto
authors: From the Departments of Restorative Neurosurgery, Psychiatry and Neurobiology, Kanazawa University Graduate School of Medical Science, 13-1 Takara-machi, Kanazawa, Japan yamashima215@gmail.com.
authors: Tetsumori
authors: T
authors: Yamashima
mesh_terms: D000818:Animals; D017209:Apoptosis; D056547:CA1 Region, Hippocampal / Q000166:cytology / Q000201:enzymology / Q000378:metabolism; D016923:Cell Death; D018840:HSP70 Heat-Shock Proteins / Q000235:genetics / Q000378:metabolism*; D008246:Lysophospholipids / Q000378:metabolism; D008247:Lysosomes / Q000201:enzymology*; D008251:Macaca; D050178:Monoglycerides / Q000378:metabolism; D009044:Motor Cortex / Q000166:cytology / Q000201:enzymology / Q000378:metabolism; D009474:Neurons / Q000166:cytology* / Q000201:enzymology / Q000378:metabolism*; D013108:Sphingomyelin Phosphodiesterase / Q000235:genetics / Q000378:metabolism*
chemical_list: D018840:HSP70 Heat-Shock Proteins; D008246:Lysophospholipids; D050178:Monoglycerides; C012786:bis(monoacylglyceryl)phosphate; C081884:heat-shock protein 70.1; D013108:Sphingomyelin Phosphodiesterase
keywords: Brain; Calpain; Cell Death; Ceramide; Lysosome; Neurodegeneration