Understanding linear ubiquitination of NEMO

Reijden, Bert van der

Constitutive NFkB activation is frequently associated with cancer development. An exact understanding of the molecular mechanisms controlling NFkB activation may provide in new therapeutic targets. An important step required for NFkB activation is the linear ubiquitination of NEMO. Ubiquitination of NEMO is catalyzed by the Linear Ubiquitin Chain Assembly Complex (LUBAC) that consists of the ubiquitin ligases HOIP, HOIL and Sharpin. How the complex functions at the molecular level is largely unknown. In a recent publication in EMBO J(1), researchers from the group of Titia Sixma (Dutch Cancer Institute, Amsterdam) showed in collaboration with researchers from the Van der Reijden group (Laboratory of Hematology) that the catalytic activity of LUBAC is entirely embedded within HOIP. The linear ubiquitin chain formation proceeds via a two-step mechanism involving transfer of ubiquitin onto HOIP and subsequent transfer onto a target ubiquitin. The latter transfer is facilitated by an unusual, newly identified,  'Linear ubiquitin chain Determining Domain' (LDD) in HOIP. Consistent with this mechanism, single point mutants in HOIP at residues involved in ubiquitin transfer completely abrogated NF-kB activation in cellular assays. The authors conclude that HOIP combines a general ubiquitin ligase mechanism with unique, LDD-dependent specificity for producing linear ubiquitin chains. 

Judith J Smit, Davide Monteferrario, Sylvie M Noordermeer, Willem J van Dijk, Bert A van der Reijden and Titia K Sixma: The E3 ligase HOIP specifies linear ubiquitin chain assembly through its RING-IBR-RING domain and the unique LDD extension. EMBOJ, 2012 Aug 3. doi: 10.1038/emboj.2012.217. [Epub ahead of print]

 Linear ubiquitination

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