Ripoptosome

The term “ripoptosome” was introduced in 2011 in two original papers published almost simultaneously: one by the research groups led by Tencho Tenev and Pascal Meier, and the other by the research groups led by Maria Feoktistova and Martin Leverkus. It therefore cannot be attributed unequivocally to a single individual.

A ripoptosome is a protein complex formed in the cytoplasm that plays a role in the decision to initiate apoptosis. Its core consists of RIPK1 (see note below), FADD, and caspase-8; its composition and function are regulated by cFLIP, among other factors. The ripoptosome acts as one ofthe “rheostats”in cell death signaling, as it can activate both apoptotic and necrotic cell death responses. The specific formation and activation of the ripoptosome in cancer cells, but not in primary cells, suggests that this complex represents a potential new target for cancer or anti-inflammatory therapy, as suggested by the potential pro-inflammatory effects of necroptosis (Schilling R et al. 2014).

The ripoptosome is strictly regulated by cIAPs, which control the intracellular assembly of RIPK1 and its association with other proteins that regulate cell death, most likely through ubiquitination. Suppression of cIAP activity leads to the accumulation of RIPK1 complexes, which ultimately triggers necroptosis through the activation of RIPK3-MLKL-dependent necrosis signaling pathways. Caspase-8 is an essential component of the ripoptosome. The actual signaling outcome (cell death or non-cell death signal) depends on the stoichiometry of the respective molecules as well as on the activity of FLIP, caspase-8, or other factors (Feoktistova M et al. 2016).

Formation and Regulation: The formation of the ripoptosome can be promoted, among other things, by genotoxic stress or the loss of cellular inhibitors of apoptosis (cIAPs). cIAPs regulate RIPK1 through ubiquitination, thereby impeding the assembly of the complex. Signals from death receptors and certain Toll-like receptors can also lead to corresponding cell death signaling pathways.

Function: If caspase-8 is sufficiently active within the ripoptosome, it can initiate apoptosis. At the same time, its activity can cleave RIPK1 and thereby prevent necroptosis. If caspase-8 activity is inhibited, necroptosis may follow if functional RIPK3 and MLKL signaling pathways are present. Which reaction predominates depends in particular on the ratio and activity of caspase-8 and the various cFLIP forms.

Induction: Various stimuli, such as genotoxic stress, binding to death receptors or Toll-like receptors (TLRs), and the degradation of cellular inhibitors of apoptosis (cIAPs), can induce the formation of a ripoptosome.

Distinction: The ripoptosome must be distinguished from the necrosome. The term “necrosome” refers to the RIPK1/RIPK3 signaling complex that is central to necroptosis.

Targeted modulation of the ripoptosome is being investigated as a potential approach in tumor and inflammation research. Preferred formation in tumor cells has been described in the models studied; however, this does not imply general tumor specificity.

"Ripoptosome" is a coined term derived from RIP (for the kinase RIPK1 involved), apoptosis (programmed cell death), and -some (protein complex).

1. Feoktistova M et al. (2011) Molecular Cell. 43:449–463. DOI: 10.1016/j.molcel.2011.06.011.
2. Feoktistova M et al. (2016) Ripoptosome Analysis by Caspase-8 Coimmunoprecipitation. Cold Spring Harb Protoc 2016:pdb.prot087403.
3. Schilling R et al. (2014) Characterization of the ripoptosome and its components: implications for anti-inflammatory and cancer therapy. Methods Enzymol 545:83–102.
4. Tenev T et al. (2011) Molecular Cell 43:432–448.