TANK-binding kinase 1 mediates phosphorylation of insulin receptor at serine residue 994: a potential link between inflammation and insulin resistance

Abstract

The IkB kinase-b (IKK-b)/nuclear factor-kB signaling pathway has been suggested to link inflammation with obesity and insulin resistance. In addition, angiotensin (Ang) II is able to induce insulin resistance and an inflammatory state through Ang II receptor type 1 (AT1R). Accordingly, we examined whether inhibition of AT1R with irbesartan (IRB) can protect against the development of insulin resistance in obese Zucker rats (OZRs). IRB-treatment improved the insulin-stimulated insulin receptor (IR) phosphorylation at tyrosine (Tyr) residues 1158, 1162, 1163 (involved in activation of the IR kinase) and at Tyr972 (involved in substrate recognition). AT1R blockade also originated a dramatic increase in the phosphorylation of Akt and glycogen synthase kinase-3b. This was accompanied by a decrease in phosphorylation of IR on serine (Ser) 994, a residue that seems to be implicated in the regulation of IR kinase in OZR. In this study, we demonstrated that Ser994 of IR is a direct substrate for TANK-binding kinase 1 (TBK1), a new member of the IKK-related kinase family. TBK1 was found to co-immunoprecipitate with the IR, in the liver of OZR supporting an in vivo association between the IR and TBK1. Interestingly, a marked increase in the association between TBK1 and the IR was found in the liver of OZR as well as in other models of insulin resistance/diabetes. Taken together, these findings suggest that TBK1 could be involved in the insulin resistance mechanism related with IR Ser994 phosphorylation in a genetic model of diabetes.

Modulation of the action of insulin by angiotensin-(1–7)

“…In support of this, the decrease in autophosphorylation of the IR induced by lipid incubation in 3T3-L1 adipocytes is prevented by blocking JNK expression [76]. In addition, we have demonstrated that obese Zucker rats displayed an increased level of phosphorylation of the IR at Ser 994 that was reduced after chronic treatment with the AT 1 R blocker irbesartan [77]. These data propose that AngIIinduced serine phosphorylation of the IR could be a mechanism behind the negative cross-talk between the insulin and AngII signalling pathways ( Figure 2).…”

Mechanism of Endogenous Regulation of the Type I Interferon Response by Suppressor of IκB Kinase ϵ (SIKE), a Novel Substrate of TANK-binding Kinase 1 (TBK1)

“…The strongest homology was evident at the SIKE sequence 184 LSISSE 189 composed of a cluster of three phosphorylation sites. When TBK1 substrates are compared, the phosphorylation pattern of TBK1 substrates has three forms as follows: singly as in Akt (22), insulin receptor (21), and optineurin (23), multiple sites but not clustered as in DDX3 (47), or multiple clustered sites as in IRF3 (15,16), IRF7 (48,49) and, as we show here, SIKE. In IRF3/7, these clustered phosphorylation sites, when modified, alter protein function, activating the transcription factor (17)(18)(19)(20).…”

“…Modified IRF3 translocates to the nucleus where it binds to the interferon ␤ enhancer and contributes to type I interferon production (15). In addition to IRF3/7, several other substrates have been identified that implicate TBK1 function in the insulin response (insulin receptor (21)), cell growth (Akt (22)) and xenophagy (optineurin (23,24)). Not surprisingly, aberrant TBK1 activity contributes to autoimmune disorders and cancers (22,(25)(26)(27).…”

Angiogenin Reduces Immune Inflammation via Inhibition of TANK-Binding Kinase 1 Expression in Human Corneal Fibroblast Cells

“…Phosphorylation of TBK1 and TNFR allows NF- κ B nuclear translocation [21], which results in the inflammatory response cascade including amplification of TBK1, IL-6 and -8, and MCP-1 [22, 67, 68]. NF- κ B plays an important role in regulating the immune response and inflammation.…”