Editors' ChoiceBiochemistry

Mutations that TANK a kinase

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Science Signaling  10 Dec 2019:
Vol. 12, Issue 611, eaba4758
DOI: 10.1126/scisignal.aba4758

ALS-associated mutations in the kinase TBK1 with the same pathological outcome affect distinct signaling pathways.

TANK-binding kinase 1 (TBK1) is a serine and threonine kinase that is implicated in innate immune responses, inflammation, selective autophagy, and cell death. Structurally, TBK1 has an N-terminal kinase domain (KD), which is followed by a ubiquitin-like domain (ULD), a scaffold dimerization domain (SDD), and a C-terminal domain. Phosphorylation of Ser172 in the activation loop is required for the activation of TBK1, which is also thought to require TBK1 dimerization. A well-characterized substrate of TBK1 is the transcriptional regulator IRF3, which drives the expression of genes encoding type I interferons (IFNs) in response to viral infections. Noting that mutations in the gene encoding TBK1 (Tbk1) are associated with sporadic and familial cases of amyotrophic lateral sclerosis (ALS), Ye et al. investigated the effects of 25 missense mutations across all domains of TBK1. The authors expressed the mutant kinases in TBK1-deficient HEK 293 cells and measured kinase abundance, Ser172 phosphorylation, substrate-specificity, and protein-protein interactions, including dimerization. Overall, this analysis showed that different mutations that lead to the same pathology in ALS affected TBK1 at different levels, including interfering with kinase activity, substrate specificity, dimerization, and interactions with autophagy receptors. Assays of heterodimers showed that mutant TBK1 proteins did not have dominant-negative effects on the wild-type kinase. Functional studies showed that monomeric TBK1 retained kinase activity, suggesting that dimerization was not required for activation; however, dimer formation increased the stability of TBK1 and the efficiency of kinase-substrate interactions. Analysis of Ser172 phosphorylation further suggests that TBK1 is activated by an unidentified upstream kinase. Together, these findings increase our understanding of the regulation and activity of TBK1 and suggest that studies of animal models expressing different TBK1 mutations may provide insights into ALS disease mechanisms.

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