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J. Exp. Med. 204 (9): 2063-2074

Copyright © 2007 by the Rockefeller University Press.

Article

MyD88-5 links mitochondria, microtubules, and JNK3 in neurons and regulates neuronal survival

Younghwa Kim1, Ping Zhou2, Liping Qian2, Jen-Zen Chuang3, Jessica Lee1, Chenjian Li2, Costantino Iadecola2, Carl Nathan1, , and Aihao Ding1

1 Department of Microbiology and Immunology, 2 Division of Neurobiology, Department of Neurology and Neuroscience, and 3 Department of Ophthalmology, Weill Medical College of Cornell University, New York, NY 10021

CORRESPONDENCE Aihao Ding: ahding{at}med.cornell.edu

Abstract: The innate immune system relies on evolutionally conserved Toll-like receptors (TLRs) to recognize diverse microbial molecular structures. Most TLRs depend on a family of adaptor proteins termed MyD88s to transduce their signals. Critical roles of MyD88-1–4 in host defense were demonstrated by defective immune responses in knockout mice. In contrast, the sites of expression and functions of vertebrate MyD88-5 have remained elusive. We show that MyD88-5 is distinct from other MyD88s in that MyD88-5 is preferentially expressed in neurons, colocalizes in part with mitochondria and JNK3, and regulates neuronal death. We prepared MyD88-5/GFP transgenic mice via a bacterial artificial chromosome to preserve its endogenous expression pattern. MyD88-5/GFP was detected chiefly in the brain, where it associated with punctate structures within neurons and copurified in part with mitochondria. In vitro, MyD88-5 coimmunoprecipitated with JNK3 and recruited JNK3 from cytosol to mitochondria. Hippocampal neurons from MyD88-5–deficient mice were protected from death after deprivation of oxygen and glucose. In contrast, MyD88-5–null macrophages behaved like wild-type cells in their response to microbial products. Thus, MyD88-5 appears unique among MyD88s in functioning to mediate stress-induced neuronal toxicity.

Abbreviations used: BAC, bacterial artificial chromosome; MAL, MyD88 adaptor–like; OGD, oxygen and glucose deprivation; PI, propidium iodide; RFP, red fluorescent protein; SAM, sterile {alpha} motif ; SARM, sterile {alpha} and HEAT/Armadillo motifs containing protein; TICAM, TIR domain–containing adaptor molecule; TIR, Toll-interleukin 1 receptor; TIRAP, TIR domain–containing adaptor protein; TIRP, TIR domain–containing protein; TLR, Toll-like receptor; TRAM, TRIF-related adaptor molecule; TRIF, TIR-domain containing adaptor inducing interferon-β.

C. Nathan and A. Ding contributed equally to this paper.

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