A HECT domain ubiquitin ligase closely related to the mammalian protein WWP1 is essential for Caenorhabditis elegans embryogenesis

The highly conserved ubiquitin/proteasome pathway controls the degradation of many critical regulatory proteins. Proteins are posttranslationally conj ugated to ubiquitin through a concerted set of reactions involving activati ng (E1), conjugating (E2), and ligase (E3) enzymes. Ubiquitination targets proteins for proteolysis via the proteasome and may regulate protein functi on independent of proteolysis. We describe the cloning and functional analy sis of new members of the HECT domain family of E3 ubiquitin ligases. Murin e Wwp1 encoded a broadly expressed protein containing a C2 domain, four WW domains, and a catalytic HECT domain. A Caenorhabditis elegans gene was clo ned encoding a HECT domain protein (CeWWP1), which was highly homologous to murine and human WWP1. Disruption of CeWwp1 via RNA interference yielded a n embryonic lethal phenotype, despite the presence of at least six addition al C. elegans genes encoding HECT domain proteins. The embryonic lethality was characterized by grossly abnormal morphogenesis during late embryogenes is, despite normal proliferation early in embryogenesis. CeWWP1 must theref ore have unique and nonredundant functions critical for embryogenesis. (C) 2000 Elsevier Science B.V. All rights reserved.