MyD88-5 and Neuronal Toxicity

Abstract

The first four members of the myeloid differentiation marker 88 (MyD88) family of cytosolic adaptor proteins are well known for their roles in mediating Toll-like receptor (TLR) signaling in the immune system. Kim et al . set out to characterize the more enigmatic fifth member of this family, MyD88-5. Northern and Western blotting demonstrated a higher abundance of MyD88-5 mRNA and protein in the brains of mice and humans than in any other organ. In human blood, real-time reverse transcription polymerase chain reaction (RT-PCR) assays showed that MyD88-5 mRNA was preferentially found in lymphocytes and not in myeloid cells. The authors developed a transgenic mouse that expressed a green fluorescent protein (GFP)-tagged MyD88-5 protein. Confocal microscopic analysis of brain sections showed that GFP fluorescence was strongest in the hippocampus and cerebellum and found only in neurons, within which MyD88-5-GFP was cytoplasmic and had a punctate distribution. When expressed in COS-1 cells, MyD88-5-GFP strongly colocalized with mitochondria. In cotransfected COS-1 cells, the authors demonstrated the colocalization of MyD88-5-GFP with c-Jun N-terminal kinase 3 (JNK3) at mitochondria, an association that was also shown in coimmunoprecipitation studies in COS-1 cells and in hippocampal lysates. JNK3 promotes apoptosis in hippocampal cells after cerebral ischemia (oxygen and nutrient deprivation), and the authors found that cell death was reduced in ischemic hippocampal slices from MyD88-5-deficient mice compared with those from wild-type mice. This study reveals the role of MyD88-5 in mediating neuronal cell death after injury and raises the interesting question of what role MyD88-5 might play in lymphocytes. Y. Kim, P. Zhou, L. Qian, J.-Z. Chuang, J. Lee, C. Li, C. Iadecola, C. Nathan, A. Ding, MyD88-5 links mitochondria, microtubules, and JNK3 in neurons and regulates neuronal survival. J. Exp. Med. 204 , 2063-2074 (2007). [Abstract] [Full Text]