Proapoptotic JNK3 (yellow) clusters near mitochondria (red) only when MyD88-5 (green) is present.

In the MyD88 family of cytosolic adaptor proteins, the newest member is the group's black sheep, according to Kim et al. (page 2063). Whereas most MyD88 proteins turn on antipathogen responses within myeloid cells, the rebel, MyD88-5, instigates cell death within neurons.

MyD88-1–4 all respond to Toll-like receptor (TLR) activation in leukocytes and stimulate innate immune responses. MyD88-5, however, does not transmit TLR signals or induce innate response genes. Two extra domains in MyD88-5 that may allow it to interact with cytoskeletal proteins hint at an entirely different function.

Kim et al. now find that the protein is not even expressed in most leukocytes and instead is found mainly in neurons. There, MyD88-5 bound to microtubules and studded the outer membranes of mitochondria. Mitochondria formed clusters when MyD88-5 expression levels were high but were unable to group when the two protein interaction domains of MyD88-5 were removed. By linking them to the microtubules, MyD88-5 probably enables the mitochondria to get around efficiently within the neuron, where these energy stores must travel long distances. But how MyD88-5 levels are controlled within the neuron remains to be determined.

MyD88-5 also recruited JNK3, a kinase whose association with mitochondria activates apoptosis in stressed cells. The stress of UV light increased the association of JNK3 with MyD88-5, and neurons from mice lacking MyD88-5 were less vulnerable to stress-induced apoptosis. The authors are now using mouse models of brain injury to investigate whether the absence of MyD88-5 saves damaged neurons during, for example, a stroke.

T cells also expressed some MyD88-5. Because these cells lack JNK3, the adaptor probably has additional binding partners.