Editors' ChoiceBiochemistry

Serine ubiquitylation

Sci. Signal.  20 Dec 2016:
Vol. 9, Issue 459, pp. ec303
DOI: 10.1126/scisignal.aam6145

Ubiquitylation is a posttranslational modification of proteins through which ubiquitin proteins are covalently attached to lysine residues in target proteins. This process of amide bond–mediated substrate attachment requires the sequential actions of three types of enzyme: an E1 enzyme activates ubiquitin, which is first transferred to the E2 ubiquitin-conjugating enzyme and then to the target protein through the action of the E3 ubiquitin ligase. This process is ATP dependent. Depending on the type of ubiquitylation (monoubiquitylation or polyubiquitylation linked through K48 or K63, for example) that occurs, the target proteins may be degraded, relocalized, or interact with specific protein partners to mediate regulatory processes. Although prokaryotes lack a ubiquitylation system, many pathogenic bacteria have evolved effector proteins that subvert protein ubiquitylation systems in infected host cells to avoid detection and destruction by the innate immune system. Noting that the Legionella pneumophila effector protein SdeA mediates the transfer of ubiquitin to host proteins in an NAD-dependent, ATP-independent manner, Bhogarju et al. investigated the mechanism and chemistry of the underlying mechanism. First, SdeA promoted the phosphoribosylation of ubiquitin, which depended on the mono-ADP-ribosyl transferase domain and a previously uncharacterized phosphodiesterase domain of SdeA. Second, SdeA catalyzed the ubiquitylation of substrate proteins by conjugating phosphoribosylated ubiquitin to a serine residue of the target protein through the formation of a phosphodiester bond. None of these reactions required the E1, E2, or E3 enzymes of the host cell ubiquitylation machinery. Indeed, in cells expressing SdeA, phosphoribosylation of ubiquitin prevented the E1 and E2 enzymes from interacting with ubiquitin, thus blocking the host ubiquitylation machinery and impairing several cellular processes that require ubiquitylation. Together, these data reveal another ubiquitylation pathway that is independent of the characterized ubiquitylation components (E1, E2, and E3) and modifies serine rather than lysine residues in target proteins. Whether such a ubiquitin phosphoribosylation system exists in mammalian cells remains to be determined.

S. Bhogaraju, S. Kalayil, Y. Liu, F. Bonn, T. Colby, I. Matic, I. Dikic, Phosphoribosylation of ubiquitin promotes serine ubiquitination and impairs conventional ubiquitination. Cell 167, 1636–1649 (2016). [PubMed]

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