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The April 2016 special issue on ubiquitin and Ubl signalling brings together a series of authoritative reviews from outstanding experts in the field. The current understanding, as well as recent advances in various aspects of ubiquitin and Ubl signalling, challenges in the fast growing field, and potentially important directions for future study, are presented. Further background information on this important topic is available through the accompanying web focus which links to related articles from across the Nature Publishing Group.
Modification of protein substrates with ubiquitin affects many aspects of cellular signalling and function. E3 ligases mediate the final step in the ubiquitination cascade, transfering ubiquitin from an E2 ubiquitin-conjugating enzyme to the substrate either directly or via a step in which the E3 ligase itself covalently binds to ubiquitin. Among the ligases that function in the latter way are the RBR family of RING-type E3 ligases, members of which include Parkin and HOIP. The hitherto resolved structures of RBR E3 ligases have all been in the auto-inhibited form. Now, Stefan Riedl and colleagues report the first structure of the fully active HOIP RBR in its transfer complex with an E2~ubiquitin conjugate. Among the insights gained is that the elongated active conformation allows the alignment of the E2 and E3 catalytic centres in a way that is ideal for ubiquitin transfer.
Compromised function of the ubiquitin-editing enzyme A20 contributes to various inflammatory syndromes and autoimmune diseases including rheumatoid arthritis, multiple sclerosis, Crohn's disease and psoriasis. Here Ingrid Wertz et al. define the molecular mechanisms by which distinct domains of A20 contribute to the regulation of inflammation and cell death.
As in other forms of selective autophagy, during mitophagy the damaged cargo — the mitochondrion — is tagged with ubiquitin chains for recognition and subsequent degradation. Specifically, the enzyme PINK1 phosphorylates ubiquitin as part of the process to activate the ubiquitin ligase enzyme parkin. Consequently, parkin can build ubiquitin chains on mitochondrial outer membrane proteins to recruit autophagy receptors. Richard Youle and colleagues report an additional layer of regulatory complexity in this pathway, with a cellular role for phosphorylated ubiquitin. Using genome editing to knockout multiple autophagy receptors, the authors find that PINK1 recruits only two such receptors, NDP52 and optineurin, to mitochondria to directly activate mitophagy, independent of parkin. NDP52 and optineurin then recruit other autophagy components. These observations call for a revision of the current model of the role of parkin in mitophagy, suggesting that it amplifies the phospho-ubiquitin signal generated by PINK1 to signal autophagy.