TANK-binding kinase 1 (TBK1) controls cell survival through PAI-2/serpinB2 and transglutaminase 2.
The decision between survival and death in cells exposed to TNF relies on a highly regulated equilibrium between proapoptotic and antiapoptotic factors. The TNF-activated antiapoptotic response depends on several transcription factors, including NF-κB and its RelA/p65 subunit, that are activated through phosphorylation-mediated degradation of IκB inhibitors, a process controlled by the IκB kinase complex. Genetic studies in mice have identified the IκB kinase-related kinase TANK-binding kinase 1 (TBK1; also called NAK or T2K) as an additional regulatory molecule that promotes survival downstream of TNF, but the mechanism through which TBK1 exerts its survival function has remained elusive. Here we show that TBK1 triggers an antiapoptotic response by controlling a specific RelA/p65 phosphorylation event. TBK1-induced RelA phosphorylation results in inducible expression of plasminogen activator inhibitor-2 (PAI-2), a member of the serpin family with known antiapoptotic activity. PAI-2 limits caspase-3 activation through stabilization of transglutaminase 2 (TG2), which cross-links and inactivates procaspase-3. Importantly, Tg2(-/-) mice were found to be more susceptible to apoptotic cell death in two models of TNF-dependent acute liver injury. Our results establish PAI-2 and TG2 as downstream mediators in the antiapoptotic response triggered upon TBK1 activation.
Department of Cancer Immunology and AIDS, Dana-Farber Cancer Institute, Boston, MA 02115, USA. mdelhase@gmail.com
Mireille
M
Delhase
Soo-Youl
SY
Kim
Ho
H
Lee
Aya
A
Naiki-Ito
Yi
Y
Chen
Eu-Ree
ER
Ahn
Kazuhiro
K
Murata
Se-Jin
SJ
Kim
Norman
N
Lautsch
Koichi S
KS
Kobayashi
Tomoyuki
T
Shirai
Michael
M
Karin
Makoto
M
Nakanishi
D000818:Animals; D017209:Apoptosis / Q000502:physiology*; D001345:Autoradiography; D053148:Caspase 3 / Q000378:metabolism; D002470:Cell Survival / Q000502:physiology*; D047369:Chromatin Immunoprecipitation; D018076:DNA, Complementary / Q000235:genetics; D004591:Electrophoresis, Polyacrylamide Gel; D005455:Fluorescent Antibody Technique; D019204:GTP-Binding Proteins / Q000235:genetics / Q000378:metabolism*; D020868:Gene Silencing; D015151:Immunoblotting; D007150:Immunohistochemistry; D047468:Immunoprecipitation; D020287:In Situ Nick-End Labeling; D051379:Mice; D018345:Mice, Knockout; D046228:Microarray Analysis; D016297:Mutagenesis, Site-Directed; D010766:Phosphorylation; D017396:Plasminogen Activator Inhibitor 2 / Q000378:metabolism*; D000091345:Protein Glutamine gamma Glutamyltransferase 2; D017346:Protein Serine-Threonine Kinases / Q000378:metabolism*; D034741:RNA, Small Interfering / Q000235:genetics; D060888:Real-Time Polymerase Chain Reaction; D051996:Transcription Factor RelA / Q000378:metabolism*; D014161:Transduction, Genetic; D011503:Transglutaminases / Q000235:genetics / Q000378:metabolism*; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism*
D018076:DNA, Complementary; D017396:Plasminogen Activator Inhibitor 2; D034741:RNA, Small Interfering; C498144:Rela protein, mouse; D051996:Transcription Factor RelA; D014409:Tumor Necrosis Factor-alpha; D000091345:Protein Glutamine gamma Glutamyltransferase 2; D011503:Transglutaminases; C498588:Tbk1 protein, mouse; D017346:Protein Serine-Threonine Kinases; D053148:Caspase 3; D019204:GTP-Binding Proteins