Abstract
Necroptotic signaling converges in the assembly of a cytosolic signaling platform, the necrosome, with the activation of its downstream effector, MLKL. RIPK1 and RIPK3, key components of the necrosome, act as signaling intermediates for the activation of MLKL. We report that RIPK3 and MLKL continuously shuttle between the nucleus and the cytoplasm, whereas RIPK1 is constitutively present in both compartments. During TNF-induced necroptosis, nuclear RIPK1 becomes ubiquitinated, after which nuclear MLKL becomes phosphorylated and oligomerized. Pharmacological inhibition of the nuclear export machinery leads to retention of RIPK3 and MLKL in the nucleus, prevents the nucleation of cytosolic RIPK3/MLKL oligomerization, and reduces cell death. Our results suggest that passage of necroptotic signaling components through the nucleus is a mechanism for regulating cytosolic necrosome formation and consequently necroptotic cell death.
Highlights
Necroptotic signaling converges in the assembly of a cytosolic signaling platform, the necrosome, with the activation of its downstream effector, mixed-lineage kinase domain like (MLKL)
As RIPK3 is a key mediator of necroptotic cell death, we reasoned that nuclear-cytoplasmic shuttling of RIPK3 could affect necroptosis
When FAS-associated via death domain protein (FADD)-deficient Jurkat cells are treated with tumor necrosis factor (TNF), they undergo RIPK3-dependent necroptosis[3, 23]
Summary
Necroptotic signaling converges in the assembly of a cytosolic signaling platform, the necrosome, with the activation of its downstream effector, MLKL. Ligand association of TNF with its cognate receptor TNF receptor (TNFR)-1 results in the formation of a membrane-associated TNFR-1 signaling complex named complex I Within this complex, ubiquitinated receptor interacting protein 1 (RIPK1) promotes activation of the NF-κB pathway. The effector mixed-lineage kinase domain like (MLKL) is recruited to the necrosome, followed by its phosphorylation by RIPK3. The RIPK3 activating function of RIPK1 can be replaced in certain circumstances by other RHIM-containing proteins, such as the TLR3/TLR4 adaptor TRIF and the DNA sensor DAI/ZBP12–14 In contrast to these heterodimeric activation models, recent findings revealed that chemically induced RIPK3 homo-oligomerization is sufficient to induce necroptosis[15,16,17]. RIPK3 and MLKL are activated in the nucleus, and after their cooperative nuclear export, they contribute to cytosolic necrosome formation. The export of RIPK3 and MLKL from the nucleus to the cytosol is important for necroptotic cell death
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