Ubiquitination and degradation of the FADDadaptor protein regulate death receptor-mediatedapoptosis and necroptosis

摘要

Fas-associated protein with death domain (FADD) is a pivotal component of death receptormediated extrinsic apoptosis and necroptosis. Here we show that FADD is regulated by makorinRing Finger Protein 1 (mKRn1) E3 ligase-mediated ubiquitination and proteasomal degradation.mKRn1 knockdown results in FADD protein stabilization and formation of the rapid deathinducing signalling complex, which causes hypersensitivity to extrinsic apoptosis by facilitatingcaspase-8 and caspase-3 cleavage in response to death signals. We also show that mKRn1 andFADD are involved in the regulation of necrosome formation and necroptosis upon caspaseinhibition. Downregulation of mKRn1 results in severe defects of tumour growth upon tumournecrosis factor-related apoptosis-inducing ligand treatment in a xenograft model using mDAmB-231 breast cancer cells. suppression of tumour growth by mKRn1 depletion is relieved bysimultaneous FADD knockdown. our data reveal a novel mechanism by which fas-associatedprotein with death domain is regulated via an ubiquitination-induced degradation pathway.