Figure 4.

Other pathways can activate RIPK3 and necroptosis. Some Toll-like receptors (e.g., TLR3, TLR4) engage the adapter protein TRIF when they are activated by their ligands. TRIF contains a RIP-homology interaction motif (RHIM) that interacts with the RHIM of RIPK3 directly, activating the kinase. ZBP1 (DAI) is an intracellular sensor of viral nucleic acids, and it too can directly activate RIPK3 via RHIM–RHIM interactions. The figure shows activation of necroptosis in the absence of RIPK1. When RIPK1 is present, the interactions are more complex. The function of MLKL is discussed below.