A new study shows that the Ras effector RALB can couple the activation of the immune system to tumor cell survival.
The oncogene Ras is known to mediate cellular transformation through a plethora of downstream effectors. Michael White and colleagues now show that one of these, the GTPase RALB, can couple the activation of the immune system to tumour cell survival.
RALB has previously been shown to promote tumour cell survival, but the downstream mediators have remained unclear. As loss of RALB induces apoptosis in cancer cells, but not normal cells, the authors carried out an RNA inhibition (RNAi)-based screen to identify a similar phenotype among the known Ral GTPase effector proteins; they identified SEC5. RALB interacts with SEC5, which is a component of the exocyst — a protein complex thought to be involved in tethering vesicles to membranes. However, the authors found that the exocyst itself was not essential for tumour cell survival. Instead, they found that SEC5 interacts with the atypical IkappaB kinase family member Tank binding kinase 1 (TBK1). The depletion of TBK1 from tumour but not normal cells induced apoptosis, mimicking the loss of RALB or SEC5. The authors also found that RALB activation promotes the interaction between SEC5 and TBK1, and this increases the activity of TBK1. Moreover, TBK1 knockout mouse embryo fibroblasts are unable to tolerate Ras overexpression, and most undergo apoptosis.
TBK1 is a central component of the signalling pathway involved in the activation of the innate immune response (activated in response to bacterial or viral infection). Surprisingly, the authors found that in normal epithelial airway cells RALB is activated by poly(I:C), a synthetic mimic of double-stranded viral RNA, or by Sendai virus, and that this response is coupled to TBK1 activation.
The authors conclude that the RALB–SEC5–TBK1 interaction is required for the innate immune response, and this pathway is commandeered in tumour cells to inhibit apoptosis in response to oncogene activation. Further investigation of this pathway should prove interesting.
Nicola McCarthy
References
Chein, Y., et al. RalB GTPase-mediated activation of the IκB family kinase TBK1 couples innate immune signalling to tumour cell survival. Cell127, 157–170 (2006) |
PubMed
