MyD88-5 links mitochondria, microtubules, and JNK3 in neurons and regulates neuronal survival.
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 co-immunoprecipitated 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.
Kim
Younghwa
Y
Department of Microbiology and Immunology, Weill Medical College of Cornell University, New York, NY 10021, USA.
Zhou
Ping
P
Qian
Liping
L
Chuang
Jen-Zen
JZ
Lee
Jessica
J
Li
Chenjian
C
Iadecola
Costantino
C
Nathan
Carl
C
Ding
Aihao
A
D000818:Animals; D002451:Cell Compartmentation; D016923:Cell Death; D002470:Cell Survival; D017124:Conserved Sequence; D019143:Evolution, Molecular; D005947:Glucose / Q000172:deficiency; D006624:Hippocampus / Q000166:cytology / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D008870:Microtubules / Q000378:metabolism*; D008928:Mitochondria / Q000201:enzymology / Q000378:metabolism*; D048057:Mitogen-Activated Protein Kinase 10 / Q000378:metabolism*; D022423:Myeloid Cells / Q000378:metabolism; D053594:Myeloid Differentiation Factor 88 / Q000172:deficiency / Q000378:metabolism*; D009474:Neurons / Q000166:cytology* / Q000201:enzymology*; D010100:Oxygen; D011485:Protein Binding; D021381:Protein Transport
D053594:Myeloid Differentiation Factor 88; D048057:Mitogen-Activated Protein Kinase 10; D005947:Glucose; D010100:Oxygen