About 10 years ago, the discovery of the Linear Ubiquitin Assembly Complex (LUBAC) revolutionized our understanding of how the master transcription factor NF-kB was activated. LUBAC a complex of the three proteins, HOIP, HOIL-1 and Sharpin, produces unique “linear” ubiquitin chains in which ubiquitins are joined to each other by peptide bonds. The linear ubiquitin chains are produced by the action of HOIP and are required to activate IKKb, the protein kinase that switches on NF-kB. LUBAC therefore has a critical role in regulating the innate immune system and the balance between cell death and cell survival.

Now Ian Kelsall and Jiazhen Zhang, two postdoc’s in Philip Cohen’s lab, have discovered the function of HOIL-1. HOIL-1 is also an E3 ligase, but has an entirely different function. It attaches the first ubiquitin to other proteins to start the synthesis of new ubiquitin chains. Ian and Roy found that, when LUBAC is recruited to immune signaling complexes, HOIL-1 and HOIP cooperate, with HOIL-1 initiating new ubiquitin chains and HOIP participating in their elongation and branching. By studying the Toll-Like Receptor signaling pathways of the innate immune system, they found that several components of the Myddosome are among the physiological substrates of both HOIL-1 and HOIP.

Even more remarkably, Ian and Jiazhen found that HOIL-1 joins ubiquitin to other proteins not by forming isopeptide bonds with the e-amino groups of lysine residues, as occurs in nearly all other E3 ligase-catalysed reactions, by instead forms ester bonds between the C-terminal carbocylate of ubiquitin and the hydroxyl side chains of serine and threonine.

These findings should enable additional proteins and biological processes to be identified in which HOIL-1 has a critical role.

The paper can be read here.