GPR108 works as a dual functional regulator to balance the TLR-triggered immune response.

For active immune response to defend the invading pathogens, TRAF6 mediates K63-linked MyD88 ubiquitination conferring its higher binding affinity to TLR4-TIRAP and inducing the downstream signaling activation through MyD88-dependent pathway (right side). At the same time, GPR108 expression is going up upon stimulation. It may mediate some unknown activation pathway in synergy with the TLR-triggered signaling. However, when signaling goes up higher, the elevated GPR108 would damp TRAF6 and reduce MyD88’s ubiquitination level which attenuates MyD88’s binding to TLR4 and collapses downstream signaling. So GPR108 suppresses the signaling by binding the de-ubiquitinated MyD88 that might possess higher affinity to GPR108 than TLR4 (left side). This regulatory loop will keep the signal activation within the appropriate range. For another level of counter regulation, TIRAP could restrict GPR108 which might act as an activator through an unknown independent pathway.