Table 2 Summary of Tbk1-deficient mouse phenotypes

Germline Tbk1^−/− [161]

Homologous-recombination targeting/knockout of exons 1-2 of Tbk1

Embryonic-lethal at E14.5 due to liver failure, resulting from aberrant death of hepatocytes induced by TNFα-RIPK1signaling.

Germline Tbk1^Δ/Δ [24, 187]

Prm1-Cre-mediated excision of Tbk1 exon 2 to yield global truncation of Tbk1, mice of 129S5 background (lack of the Tnfrsf1b gene) to circumvent embryonic-lethal phenotype of Tbk1 deficiency [187]

Exhibit mononuclear and granulomatous cell infiltrates in multiple organs and inflammatory cell infiltrates in their skin; hypersensitive to LPS stimulation [187].

Reduced weight gain and pancreatic abnormalities amid high-fat diet; increased insulin sensitivity due to absence of Tbk1-mediated inhibition of insulin receptor signaling [24].

Tbk1^fl/fl, neuron-specific [207]

Nestin-Cre

ALS/FTD symptoms as demonstrated by cognitive and locomotor deficits. Resulting from impaired autophagy in motor neuron-like cells

Tbk1^fl/fl, adipocyte-specific [39]

Adiponectin-Cre

Attenuates HFD-induced obesity by increasing energy expenditure, as TBK1 directly inhibits AMPK to suppress respiration and increase energy storage; increased inflammation and decreased insulin sensitivity because TBK1 represses NF-κB activity.

Tbk1^fl/fl, myeloid cell-specific [215,216,217,218]

Lyz2-Cre

In IAV infection model, knockout mice display dampened immune response to IAV and improved survival. This is due to reduced recruitment of CD64⁺SiglecF⁻Ly6C^hi inflammatory macrophages, and reduced expression of inflammatory cytokines in the bronchoalveolar lavage fluid, and reduced expression of both IRF- and NF-κB-target genes in the lung [217].

In ALS model, knockout mice develop accelerated ALS due to the increased inflammatory cell infiltration, which induces motor deficits and axonal damage [216].

Eight month-old mice displayed adipocytic hypertrophy, increased M1/decreased M2 macrophage infiltration, and increased pro-IL-1β protein level in eWAT. Four week-old mice fed HFD developed liver abnormalities consistent with NAISH. Mice also displayed insulin-glucose axis dysfunction and increased disease severity in a DSS-induced colitis model [215].

Tbk1^fl/fl, T cell-specific [2]

Cd4-Cre

Impaired T-cell migration (T_eff egress from draining lymph nodes) due to the enhanced activation of AKT-mTORC1 signaling axis. In a neuroinflammatory autoimmunity model, Tbk1 knockout in T cells represses the development of experimental autoimmune encephalomyelitis (EAE).

Tbk1^fl/fl, dendritic cell-specific [154]

CD11c-Cre

Upregulation of costimulatory molecules, increased T-cell-priming activity and upregulation of a subset of genes by IFNAR. Mice develop autoimmune symptoms and display enhanced antitumor immunity.

Tbk1^fl/fl, B cell-specific [78]

Cd19-Cre

Uncontrolled production of IgA and the development of IgA nephropathy-like disease; activation of the non-canonical NF-κB pathway in B cells.

Tbk1^fl/fl, intestinal epithelia-specific [219]

Villin-Cre

Increased MT1 expression; increased number of Th17 cells in lamina propria; increased production of IL-1β by intestinal macrophages; increased number/size of intestinal neoplasms.

Tbk11^fl/fl, hepatocyte-specific [144]

Albumin-Cre

Increased liver lipid due to reduced β-oxidation of acyl-CoAs/fatty acids; fasting-state mitochondrial localization of ACSL1 is impeded.