TAK1, more than just innate immunity

Dai, Liang; Thu, Chan Aye; Liu, Xin Yu; Xi, Jia Jia; Cheung, Pierina

doi:10.1002/iub.1078

Cited by 154 publications

(147 citation statements)

References 72 publications

Supporting

Mentioning

145

Contrasting

Order By: Relevance

“…TAK1 is a central regulator of NF-κB activation, which is an important mediator of cell survival (20,21). Consistent with this, loss of TAK1 has been shown to increase the sensitivity of cells for induction of apoptotic cell death (23,25,28,38).…”

Section: Discussionmentioning

confidence: 70%

“…In searching for potential targets that can be exploited to modify both proinflammatory signaling in adipocytes and adipocyte turnover, we focused on TGF-β-activated kinase 1 (TAK1), which couples TLRs and various cytokine receptors to the activation of the NF-κB pathway as well as to mitogen-activated kinases, such as p38 and JNK (20,21). Thereby, TAK1 plays a well-established role in proinflammatory signaling.…”

Section: Introductionmentioning

confidence: 99%

See 1 more Smart Citation

Increased apoptosis and browning of TAK1-deficient adipocytes protects against obesity

Sassmann-Schweda¹,

Singh²,

Tang³

et al. 2016

JCI Insight

View full text Add to dashboard Cite

Section: Discussionmentioning

confidence: 70%

Section: Introductionmentioning

confidence: 99%

Increased apoptosis and browning of TAK1-deficient adipocytes protects against obesity

Sassmann-Schweda¹,

Singh²,

Tang³

et al. 2016

JCI Insight

View full text Add to dashboard Cite

“…Activation of IKKβ leads to the activation IKKα, degradation of IκBα, and finally, activation of NF-κB-driven transcription. The known direct substrates of TAK1 are limited to these protein kinases, TAK1 binding protein 1 (TAB1), and an additional protein kinase, AMPK (4,5). TAK1 is primarily viewed as an initiator of kinase signaling cascades that lead to transcription factor activation.…”

mentioning

confidence: 99%

Innate immunity kinase TAK1 phosphorylates Rab1 on a hotspot for posttranslational modifications by host and pathogen

Levin

Hertz

Burlingame

et al. 2016

Proc. Natl. Acad. Sci. U.S.A.

View full text Add to dashboard Cite

TGF-β activated kinase 1 (TAK1) is a critical signaling hub responsible for translating antigen binding signals to immune receptors for the activation of the AP-1 and NF-κB master transcriptional programs. Despite its importance, known substrates of TAK1 are limited to kinases of the MAPK and IKK families and include no direct effectors of biochemical processes. Here, we identify over 200 substrates of TAK1 using a chemical genetic kinase strategy. We validate phosphorylation of the dynamic switch II region of GTPase Rab1, a mediator of endoplasmic reticulum to Golgi vesicular transport, at T75 to be regulated by TAK1 in vivo. TAK1 preferentially phosphorylates the inactive (GDP-bound) state of Rab1. Phosphorylation of Rab1 disrupts interaction with GDP dissociation inhibitor 1 (GDI1), but not guanine exchange factor (GEF) or GTPaseactivating protein (GAP) enzymes, and is exclusive to membranelocalized Rab1, suggesting phosphorylation may stimulate Rab1 membrane association. Furthermore, we found phosphorylation of Rab1 at T75 to be essential for Rab1 function. Previous studies established that the pathogen Legionella pneumophila is capable of hijacking Rab1 function through posttranslational modifications of the switch II region. Here, we present evidence that Rab1 is regulated by the host in a similar fashion, and that the innate immunity kinase TAK1 and Legionella effectors compete to regulate Rab1 by switch II modifications during infection.

show abstract

“…Interestingly, TRAF3 bound only to the C-terminal TAB2/3-binding domain (TAB2/3 BD) of TAK1, which was also critical for its interaction with TAB2 and TAB3 and for subsequent activation of TAK1 ( Figure S8C). 27 However, whether the TAK1-TRAF3 interaction is sufficient to mediate TRAF3/TAK1-mediated neuronal death remains unknown. Thus, we constructed an adenoviral vector harboring TRAF3 with a mutant TRAF domain (AdTRAF3-M).…”

Section: Traf3-tak1 Interaction Is Required For Traf3-dependent Cerebmentioning

confidence: 99%

Neuron-Specific Tumor Necrosis Factor Receptor–Associated Factor 3 Is a Central Regulator of Neuronal Death in Acute Ischemic Stroke

Gong

Guo

et al. 2015

Hypertension

View full text Add to dashboard Cite

Neuronal death after ischemic stroke involves multiple pathophysiological events, as well as a complex molecular mechanism. Inhibiting a single therapeutic target that is involved in several ischemic signaling cascades may be a promising strategy for stroke management. Here, we report the versatile biological roles of tumor necrosis factor receptor–associated factor 3 (TRAF3) in ischemic stroke. Using several genetically manipulated mouse strains, we also demonstrated that TRAF3 inhibition can be neuroprotective. TRAF3 expression, which is robustly induced in response to ischemia/reperfusion (I/R) injury, was detected in neurons. Overexpression of TRAF3 in neurons led to aggravated neuronal loss and enlarged infarcts; these effects were reversed in TRAF3-knockout mice. Neuronal TRAF3 also contributed to c-Jun kinase–, nuclear factor κB– and Rac-1–induced neuronal death, inflammation, and oxidative stress. Mechanistically, we showed that TRAF3 interacts with transforming growth factor-β–activated kinase 1 (TAK1) and potentiates phosphorylation and activation of TAK1. Phosphorylated TAK1 sequentially initiated activation of nuclear factor κB, Rac-1/NADPH oxidase, and c-Jun kinase/c-Jun signaling cascades. Using a combination of adenoviruses encoding dominant-negative TAK1 and the TAK1 inhibitor 5Z-7-oxozeaenol, we demonstrated that the TRAF3-mediated activation of ischemic cascades was TAK1-dependent. More importantly, the adverse phenotypes observed in TRAF3-overexpressing mice were completely reversed when the TRAF3–TAK1 interaction was prevented. Therefore, we have shown that TRAF3 is a central regulator of ischemic pathways, including nuclear factor κB, Rac-1, and c-Jun kinase signaling, via its interaction with and activation of TAK1. Furthermore, certain components of the TRAF3–TAK1 signaling pathway are potentially promising therapeutic targets in ischemic stroke.

show abstract

TAK1, more than just innate immunity

Cited by 154 publications

References 72 publications

Increased apoptosis and browning of TAK1-deficient adipocytes protects against obesity

Increased apoptosis and browning of TAK1-deficient adipocytes protects against obesity

Innate immunity kinase TAK1 phosphorylates Rab1 on a hotspot for posttranslational modifications by host and pathogen

Neuron-Specific Tumor Necrosis Factor Receptor–Associated Factor 3 Is a Central Regulator of Neuronal Death in Acute Ischemic Stroke

Contact Info

Product

Resources

About