Innate immune activation by microbial detection receptors is a complex process involving at least 100 proteins and multiple signaling pathways. Although there continues to be a need to identify additional regulators of host-microbe interactions, a larger conceptual challenge is our lack of understanding of how the known regulators interact in space and time. This review offers a framework to explain the long appreciated (but poorly understood) observation that innate immune signaling pathways are activated from multiple organelles. Using the Toll-like receptors (TLRs) and the retinoic acid-inducible gene 1 protein (RIG-I)-like receptors (RLRs) as examples, I propose that the receptors do not necessarily define the sites of signaling. Rather, a structurally unrelated class of proteins called 'sorting adaptors' functions in this capacity.
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