{"doi":"10.1016/j.jbc.2021.101244","title":"TBK1 has a new Akt","abstract":"TANK-binding kinase 1 (TBK1) is a noncanonical IκB kinase that plays an essential role in the innate immune response to foreign pathogens. Recent studies have highlighted additional roles for TBK1 in the regulation of metabolism, although the mechanisms of this regulation have not been well characterized. In a recent issue, Tooley et al. demonstrated that TBK1-dependent activation of downstream kinase Akt is mediated via mechanistic target of rapamycin complex 2. This novel action of TBK1 reveals a key role for this kinase in the regulation of cellular metabolism and growth by diverse environmental inputs. TANK-binding kinase 1 (TBK1) is a noncanonical IκB kinase that plays an essential role in the innate immune response to foreign pathogens. Recent studies have highlighted additional roles for TBK1 in the regulation of metabolism, although the mechanisms of this regulation have not been well characterized. In a recent issue, Tooley et al. demonstrated that TBK1-dependent activation of downstream kinase Akt is mediated via mechanistic target of rapamycin complex 2. This novel action of TBK1 reveals a key role for this kinase in the regulation of cellular metabolism and growth by diverse environmental inputs. TANK-binding kinase 1 (TBK1), a serine/threonine kinase that belongs to the noncanonical IκB kinase family, plays an essential role in the innate immune response to viral and bacterial pathogens by regulating the type I interferon–mediated T cell response (1Fitzgerald K.A. McWhirter S.M. Faia K.L. Rowe D.C. Latz E. Golenbock D.T. Coyle A.J. Liao S.M. Maniatis T. IKKepsilon and TBK1 are essential components of the IRF3 signaling pathway.Nat. Immunol. 2003; 4: 491-496Crossref PubMed Scopus (1940) Google Scholar). Although TBK1 has been most widely studied in this context, more recent investigations using tissue-specific KO mice and drugs that inhibit kinase activity have revealed novel roles for this kinase in nonimmune cells, particularly at the intersection of immunity and metabolism. For example, TBK1 expression and activity are induced in adipose tissue in obesity by elevated expression of proinflammatory cytokines such as tumor necrosis factor α (2Zhao P. Saltiel A.R. Interaction of adipocyte metabolic and immune functions through TBK1.Front. Immunol. 2020; 11: 592949Crossref PubMed Scopus (2) Google Scholar). TBK1 contributes to obesity by repressing energy expenditure and increasing anabolic functions as determined from analysis of mice with conditional adipose cell KO of TBK1 (3Zhao P. Wong K.I. Sun X. Reilly S.M. Uhm M. Liao Z. Skorobogatko Y. Saltiel A.R. TBK1 at the crossroads of inflammation and energy homeostasis in adipose tissue.Cell. 2018; 172: 731-743.e712Abstract Full Text Full Text PDF PubMed Scopus (97) Google Scholar). TBK1 has also been reported to promote activation of Akt, a central kinase involved in metabolic regulation (4Manning B.D. Toker A. AKT/PKB signaling: Navigating the network.Cell. 2017; 169: 381-405Abstract Full Text Full Text PDF PubMed Scopus (1393) Google Scholar). However, the mechanism by which TBK1 regulates Akt has remained unclear. Akt is an essential regulator of glucose metabolism and plays an important role in controlling cellular glucose uptake and utilization through both positive and negative regulatory actions (4Manning B.D. Toker A. AKT/PKB signaling: Navigating the network.Cell. 2017; 169: 381-405Abstract Full Text Full Text PDF PubMed Scopus (1393) Google Scholar). Phosphorylation of Akt on T308 in its activation loop stimulates kinase activity, and phosphorylation on S473 further enhances activity and determines substrate specificity (4Manning B.D. Toker A. AKT/PKB signaling: Navigating the network.Cell. 2017; 169: 381-405Abstract Full Text Full Text PDF PubMed Scopus (1393) Google Scholar). Although it had been previously reported that TBK1 can directly phosphorylate Akt at S473 and T308 in in vitro kinase assays, the ability of TBK1 to mediate these phosphorylation eve","journal":"Journal of Biological Chemistry","year":2021,"id":212219,"datarank":0.0,"base_score":0.0,"endowment":0.0,"self_citation_contribution":0.0,"citation_network_contribution":0.0,"self_endowment_contribution":0.0,"citer_contribution":0.0,"corpus_percentile":null,"corpus_rank":null,"citation_count":1,"citer_count":0,"citers_with_citation_signal":0,"citers_with_endowment":0,"datacite_reuse_total":0,"is_dataset":false,"is_dataset_confidence":0.9591,"is_data_producer":false,"deposit_databanks":null,"is_oa":true,"file_count":0,"downloads":0,"has_version_chain":false,"published_date":"2021-01-01","fair_score":null,"fair_percentile":null,"algorithm_id":"datarank_citation_only_1hop_v6","ranking_scope":"data_only","authors":[{"id":802177,"name":"Leslie M. 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