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

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.

Toll-like receptors, signaling adapters and regulation of the pro-inflammatory response by PI3K

“…17,18 Studies using SARM-deficient mice demonstrated SARM is mainly expressed in the brain, and SARMdeficient macrophages were functionally normal when stimulated with TLR ligands. 17,19 Therefore, it is proposed that it could play different roles between the two species. 17 Indeed, SARM-deficient mice were found to be highly susceptible to infection with West Nile virus and displayed enhanced viral replication in the brain, decreased activation of microglia and, ultimately, increased mortality.…”

SARM1-specific motifs in the TIR domain enable NAD + loss and regulate injury-induced SARM1 activation

“…Augmenting NAD + biosynthetic pathways protects injured axons from degeneration, suggesting this step is crucial in axonal breakdown (5,6). In addition to local axon degeneration, SARM1 promotes neuronal cell death in response to mitochondrial toxins, oxygen glucose deprivation, and viral infection (7)(8)(9)(10). Activated SARM1 can induce cell death independent of other known programmed cell death programs in a pathway termed sarmoptosis.…”

Innate immune responses regulate morphogenesis and degeneration: roles of Toll-like receptors and Sarm1 in neurons

“…The predominantly neuronal expression of Sarm1 distinguishes it from all other TIR domain-containing adaptors involved in TLR signaling [12,14] . Consistent with the original fi nding regarding the involvement of Sarm1 in innate immunity [47] , Sarm1 knockdown in the mouse brain disrupts the expression levels of infl ammatory and antiviral cytokines.…”

“…associates with JNK3, recruits JNK3 to mitochondria, and regulates cell death after deprivation of glucose and oxygen [14] . This discovery has recently been confi rmed by other studies [50,51] .…”

“…In addition to TLRs, neurons also express the critical TIR domain-containing adaptors, which transduce the downstream signals of TLRs, including myeloid differentiation primary response gene 88 (MyD88), TIR domain-containing adapter-inducing IFN-β (Trif) [10] and sterile alpha and HEAT/Armadillo motif-containing 1 (Sarm1) [12] . Notably, Sarm1 is predominantly expressed in neurons rather than astrocytes, microglia, or the peripheral immune system [12][13][14] . This characteristic is unique to Sarm1 among all of the known TLRs and TIR domain-containing adaptors.…”