title: Proapoptotic activities of protein disulfide isomerase (PDI) and PDIA3 protein, a role of the Bcl-2 protein Bak.
abstract: Protein disulfide isomerase (PDI) family proteins are classified as enzymatic chaperones for reconstructing misfolded proteins. Previous studies have shown that several PDI members possess potential proapoptotic functions. However, the detailed molecular mechanisms of PDI-mediated apoptosis are not completely known. In this study, we investigated how two members of PDI family, PDI and PDIA3, modulate apoptotic signaling. Inhibiting PDI and PDIA3 activities pharmacologically alleviates apoptosis induced by various apoptotic stimuli. Although a decrease of PDIA3 expression alleviates apoptotic responses, overexpression of PDIA3 exacerbates apoptotic signaling. Importantly, Bak, but not Bax, is essential for PDIA3-induced proapoptotic signaling. Furthermore, both purified PDI and PDIA3 proteins induce Bak-dependent, but not Bax-dependent, mitochondrial outer membrane permeabilization in vitro, probably through triggering Bak oligomerization on mitochondria. Our results suggest that both of PDI and PDIA3 possess Bak-dependent proapoptotic function through inducing mitochondrial outer membrane permeabilization, which provides a new mechanism linking ER chaperone proteins and apoptotic signaling.
authors.affiliation: From the Molecular Targets Program, Departments of Medicine, Pharmacology, and Toxicology, University of Louisville, Louisville, Kentucky 40202 and.
authors.forename: Guoping
authors.initials: G
authors.lastname: Zhao
authors.affiliation: the Second Hospital, Jilin University, Changchun, Jilin Province, China 130041.
authors.forename: Huayi
authors.initials: H
authors.lastname: Lu
authors.affiliation: From the Molecular Targets Program, Departments of Medicine, Pharmacology, and Toxicology, University of Louisville, Louisville, Kentucky 40202 and chi.li@louisville.edu.
authors.forename: Chi
authors.initials: C
authors.lastname: Li
mesh_terms: D000818:Animals; D017209:Apoptosis; D055162:Biocatalysis; D005455:Fluorescent Antibody Technique; D051379:Mice; D019704:Protein Disulfide-Isomerases / Q000378:metabolism*; D050998:bcl-2 Homologous Antagonist-Killer Protein / Q000502:physiology*
chemical_list: C494773:Bak1 protein, mouse; D050998:bcl-2 Homologous Antagonist-Killer Protein; C513195:Pdia3 protein, mouse; D019704:Protein Disulfide-Isomerases
keywords: Apoptosis; B Cell Lymphoma 2 (Bcl-2); Bak; Bax; Endoplasmic Reticulum (ER); Mitochondrial Outer Membrane Permeabilization; Protein Disulfide Isomerase