RalB GTPase-mediated activation of the IkappaB family kinase TBK1 couples innate immune signaling to tumor cell survival.
The monomeric RalGTPases, RalA and RalB are recognized as components of a regulatory framework supporting tumorigenic transformation. Specifically, RalB is required to suppress apoptotic checkpoint activation, the mechanistic basis of which is unknown. Reported effector proteins of RalB include the Sec5 component of the exocyst, an octameric protein complex implicated in tethering of vesicles to membranes. Surprisingly, we find that the RalB/Sec5 effector complex directly recruits and activates the atypical IkappaB kinase family member TBK1. In cancer cells, constitutive engagement of this pathway, via chronic RalB activation, restricts initiation of apoptotic programs typically engaged in the context of oncogenic stress. Although dispensable for survival in a nontumorigenic context, this pathway helps mount an innate immune response to virus exposure. These observations define the mechanistic contribution of RalGTPases to cancer cell survival and reveal the RalB/Sec5 effector complex as a component of TBK1-dependent innate immune signaling.
Chien
Yuchen
Y
Department of Cell Biology, University of Texas Southwestern Medical Center, 5323 Harry Hines Blvd., Dallas, TX 75390, USA.
Kim
Sungchan
S
Bumeister
Ron
R
Loo
Yueh-Ming
YM
Kwon
Sung Won
SW
Johnson
Cynthia L
CL
Balakireva
Mirey G
MG
Romeo
Yves
Y
Kopelovich
Levy
L
Gale
Michael
M
Yeaman
Charles
C
Camonis
Jacques H
JH
Zhao
Yingming
Y
White
Michael A
MA
D000818:Animals; D017209:Apoptosis / Q000502:physiology; D002352:Carrier Proteins / Q000235:genetics / Q000378:metabolism*; D002470:Cell Survival; D002471:Cell Transformation, Neoplastic; D004789:Enzyme Activation; D006367:HeLa Cells; D006801:Humans; D007113:Immunity, Innate / Q000502:physiology*; D051379:Mice; D018345:Mice, Knockout; D046912:Multiprotein Complexes; D009369:Neoplasms / Q000378:metabolism*; D017346:Protein Serine-Threonine Kinases / Q000235:genetics / Q000378:metabolism*; D034741:RNA, Small Interfering / Q000235:genetics / Q000378:metabolism; D011993:Recombinant Fusion Proteins / Q000235:genetics / Q000378:metabolism; D015398:Signal Transduction / Q000502:physiology*; D033921:Vesicular Transport Proteins; D020725:ral GTP-Binding Proteins / Q000235:genetics / Q000378:metabolism*
D002352:Carrier Proteins; C470182:EXOC2 protein, human; D046912:Multiprotein Complexes; D034741:RNA, Small Interfering; C483163:Ralb protein, human; D011993:Recombinant Fusion Proteins; D033921:Vesicular Transport Proteins; D017346:Protein Serine-Threonine Kinases; C403191:TBK1 protein, human; D020725:ral GTP-Binding Proteins