Mind bomb 1 regulation of cFLIP interactions

Liguo Zhang, Patricia J. Gallagher

Research output: Contribution to journalArticle

12 Scopus citations

Abstract

Mind bomb 1 (Mib1) is a multidomain E3 ligase that directs ubiquitination of the Notch ligands Delta and Jagged to promote their endocytosis. Here we examine Notch-independent functions of Mib1 and find that its activities are linked to the initiation of the extrinsic cell death pathway. Expression of Mib1 induces a spontaneous, caspase-dependent cell death. Consistent with this, depletion of endogenous Mib1 decreases tumor-necrosis factor (TNF)-induced cell death. Mib1 was found to bind to cellular Fas-associated death domain (FADD)-like IL-1b converting enzyme (FLICE)-like inhibitory proteins (cFLIP-L and cFLIP-S), whereas only cFLIP-s can inhibit Mib1-induced cell death. The interaction between Mib1 and cFLIP decreases the association of caspase-8 with cFLIP, which activates caspase-8 and induces cell death. Collectively, these results suggest that in addition to a central role in Notch signaling, Mib1 has an important role in regulating the extrinsic cell death pathway.

Original languageEnglish (US)
Pages (from-to)C1275-C1283
JournalAmerican Journal of Physiology - Cell Physiology
Volume297
Issue number5
DOIs
StatePublished - Nov 1 2009

Keywords

  • Apoptosis
  • Caspase-8
  • Cell death
  • E3 ubiquitin ligase
  • Notch
  • Ubiquitination

ASJC Scopus subject areas

  • Cell Biology
  • Physiology

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