HECT, C2 And WW Domain Containing E3 Ubiquitin Protein Ligase 2 (HECW2)

Expression of p73 is maintained at low levels in mammalian cells, and cellular activation of p73 is usually controlled at the protein level. NEDL2 contains a C2 domain at its NH(2)-terminus, two WW domains, and a HECT domain at its COOH-terminus. As expected, NEDL2 catalyzed the ubiquitination of bacterial cellular proteins in vitro. Reciprocal co-immunoprecipitation experiments and in vitro pull-down assays revealed that NEDL2 bound to p73, which carries two putative PY motifs. p73 was efficiently ubiquitinated but stabilized in a NEDL2-dependent manner. Accordingly, p73 decayed at faster rates in the absence of NEDL2 than in its presence. Consistent with the NEDL2-mediated stabilization of p73, NEDL2 enhanced the p73-dependent transcriptional activation. NEDL2 activates the function of p73 by increasing its stability.