RESUMO
Autoantibodies from autistic spectrum disorder (ASD) patients react with multiple proteins expressed in the brain. One such autoantibody targets myelin basic protein (MBP). ASD patients have autoantibodies to MBP of both the IgG and IgA classes in high titers, but no autoantibodies of the IgM class. IgA autoantibodies act as serine proteinases and degrade MBP in vitro. They also induce a decrease in long-term potentiation in the hippocampi of rats either perfused with or previously inoculated with this IgA. Because this class of autoantibody causes myelin sheath destruction in multiple sclerosis (MS), we hypothesized a similar pathological role for them in ASD.
Assuntos
Transtorno Autístico/sangue , Hipocampo/citologia , Imunoglobulina A/sangue , Imunoglobulina A/farmacologia , Proteína Básica da Mielina/imunologia , Transmissão Sináptica/efeitos dos fármacos , Adolescente , Animais , Transtorno Autístico/imunologia , Transtorno Autístico/fisiopatologia , Encéfalo/efeitos dos fármacos , Encéfalo/imunologia , Encéfalo/metabolismo , Criança , Pré-Escolar , Inibidores de Cisteína Proteinase/farmacologia , Relação Dose-Resposta a Droga , Feminino , Humanos , Imunoglobulina A/efeitos dos fármacos , Técnicas In Vitro , Leupeptinas/farmacologia , Potenciação de Longa Duração/efeitos dos fármacos , Masculino , Técnicas de Patch-Clamp , Proteólise/efeitos dos fármacos , Ratos , Ratos Sprague-DawleyRESUMO
The glucose-regulated protein 78 (GRP78) is a plasminogen (Pg) receptor on the cell surface. In this study, we demonstrate that GRP78 also binds the tissue-type plasminogen activator (t-PA), which results in a decrease in K(m) and an increase in the V(max) for both its amidolytic activity and activation of its substrate, Pg. This results in accelerated Pg activation when GRP78, t-PA, and Pg are bound together. The increase in t-PA activity is the result of a mechanism involving a t-PA lysine-dependent binding site in the GRP78 amino acid sequence (98)LIGRTWNDPSVQQDIKFL(115). We found that GRP78 is expressed on the surface of neuroblastoma SK-N-SH cells where it is co-localized with the voltage-dependent anion channel (VDAC), which is also a t-PA-binding protein in these cells. We demonstrate that both Pg and t-PA serve as a bridge between GRP78 and VDAC bringing them together to facilitate Pg activation. t-PA induces SK-N-SH cell proliferation via binding to GRP78 on the cell surface. Furthermore, Pg binding to the COOH-terminal region of GRP78 stimulates cell proliferation via its microplasminogen domain. This study confirms previous findings from our laboratory showing that GRP78 acts as a growth factor-like receptor and that its association with t-PA, Pg, and VDAC on the cell surface may be part of a system controlling cell growth.
