TBK1 Suppresses RIPK1-Driven Apoptosis and Inflammation during Development and in Aging

Abstract

Aging is a major risk factor for both genetic and sporadic neurodegenerative disorders. However, it is unclear how aging interacts with genetic predispositions to promote neurodegeneration. Here, we investigate how partial loss of function of TBK1, a major genetic cause for amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD) comorbidity, leads to age-dependent neurodegeneration. We show that TBK1 is an endogenous inhibitor of RIPK1 and the embryonic lethality of Tbk1 mice is dependent on RIPK1 kinase activity. In aging human brains, another endogenous RIPK1 inhibitor, TAK1, exhibits a marked decrease in expression. We show that in Tbk1 mice, the reduced myeloid TAK1 expression promotes all the key hallmarks of ALS/FTD, including neuroinflammation, TDP-43 aggregation, axonal degeneration, neuronal loss, and behavior deficits, which are blocked upon inhibition of RIPK1. Thus, aging facilitates RIPK1 activation by reducing TAK1 expression, which cooperates with genetic risk factors to promote the onset of ALS/FTD.

OTULIN prevents liver inflammation and hepatocellular carcinoma by inhibiting FADD- and RIPK1 kinase-mediated hepatocyte apoptosis

“…On the one hand, it promotes the transcriptional upregulation of anti-apoptotic proteins by NF-κB, which protect cells from RIPK1 kinase-independent apoptosis (Wang et al, 2008). On the other hand, it allows the phosphorylation of RIPK1 by IKKα/β- and TBK1/IKKε, which was shown to protect cells from RIPK1 kinase-dependent apoptosis (Dondelinger et al, 2015, 2019; Lafont et al, 2018; Xu et al, 2018; Ting and Bertrand, 2016). While several studies have reported the importance of proper TNF signaling for the maintenance of liver homeostasis and to prevent liver inflammation and inflammation-induced HCC (Luedde et al, 2014), our study did not identify TNF as a driving cytokine in the liver pathology of OTULIN LPC-KO mice.…”

“…The adaptor protein NEMO binds to these linear chains and brings the kinases IKKα and IKKβ to the complex, thereby allowing activation of the NF-κB pathway. NEMO recruitment to the complex also enables activation of the kinases TBK1/IKKε, which may regulate NF-κB activation (Clark et al, 2011; Lafont et al, 2018; Xu et al, 2018). Upon activation, the MAPK and NF-κB pathways drive expression of a large set of genes, including pro-inflammatory genes (Ting and Bertrand, 2016).…”

“…Indeed, apart from pro-inflammatory molecules, activation of NF-κB also leads to the transcriptional upregulation of anti-apoptotic proteins, which protect cells from RIPK1 kinase-independent apoptosis (Wang et al, 2008). In addition, the linear ubiquitin-dependent phosphorylation of RIPK1 by IKKα/β- and TBK1/IKKε was shown to protect cells from RIPK1 kinase-dependent apoptosis (Dondelinger et al, 2015, 2019; Lafont et al, 2018; Xu et al, 2018; Ting and Bertrand, 2016). Consequently, when these protective brakes are compromised, such as following LUBAC deficiency (Peltzer et al, 2014, 2018) (Priem et al CDDis 2019), activated TRADD and RIPK1 dissociate from complex I, and respectively induce RIPK1 kinase-independent and -dependent apoptotic cascades through association with Fas-associated death domain (FADD) protein and procaspase-8 to form the cytosolic death inducing complex II.…”

Metformin mediates cardioprotection against aging‐induced ischemic necroptosis

“…Aging hearts work on the edge of disease (Dai, Chen, Johnson, Szeto, & Rabinovitch, 2012;Xu et al, 2018). Aging is associated not only with a progressive decline in physical function, but also with a significant increase in the risk of many disabilities and even death.…”

Arf1-Ablation-Induced Neuronal Damage Promotes Neurodegeneration Through an NLRP3 Inflammasome–Meningeal γδ T cell–IFNγ-Reactive Astrocyte Pathway

“…In recent years, scientists began to realize the importance of immune cells in NDs. However, most studies have focused on the nonspecific, innate immune cells (mostly microglia) (Heneka et al, 2013;Hong et al, 2016;Ising et al, 2019;Ito et al, 2016;Keren-Shaul et al, 2017;Labzin et al, 2018;Singhal et al, 2014;Xu et al, 2018). More recently, a few of reports revealed T cells' contributions to NDs (Gate et al, 2020;Jelcic et al, 2018;Lodygin et al, 2019;Shichita et al, 2009;Sulzer et al, 2017;Sun et al, 2018).…”