The Phosphorylation-Dependent Regulation of Mitochondrial Proteins in Stress Responses
Figure 5
Necrosis signaling pathways. (a) Necrosis is induced downstream of death domain-containing receptors, including TNF receptors 1 (TNFR1) and TNFR2. When TNFα binds to TNFR1, RIP1 is recruited to the activated TNFR1. In this receptor-associated complex, E3 ligase cellular inhibitor of apoptosis proteins (cIAPs) mediate the Lys63-linked polyubiquitin of RIP1, activating the NF-κB pathway. Conversely, when the Lys63-linked polyubiquitin is removed by deubiquitinating enzymes, including CYLD, RIP1 functions as a cell death inducer rather than as a survival-promoting factor. When caspase 8 activity is blocked by inhibitors, such as a pan-caspase inhibitor or Z-VAD-fmk, or by the genetic ablation of caspase 8 itself, RIP1 interacts with RIP3 and forms a necrosis-inducing complex. RIP1 and RIP3 become phosphorylated and activated in this complex. Although the kinase activity of RIP1 is not required to activate the NF-κB pathway, its kinase activity is essential for necrosis induction. (b) The mitochondrial Ser/Thr protein phosphatase PGAM5 is a substrate of RIP3. The RIP3-mediated phosphorylation of PGAM5 enhances its protein phosphatase activity. Once activated by phosphorylation, PGAM5 dephosphorylates and activates the mitochondrial fission regulator Drp1, promoting mitochondrial fission and subsequent necrosis. PGAM5 has two splice variants in humans, PGAM5L and PGAM5S, each of which appears to have different functions in necrosis (see text for details).
