Regulation of phosphoribosyl ubiquitination by a calmodulin-dependent glutamylase

Article

关键词: STRUCTURAL BASIS;    ENDOPLASMIC-RETICULUM;    LEGIONELLA;    PROTEINS;    DEUBIQUITINASE;    CATALYZES;    SYSTEM;   

DOI  :  10.1038/s41586-019-1439-1

来源: SCIE

【 摘 要 】

The bacterial pathogen Legionella pneumophila creates an intracellular niche permissive for its replication by extensively modulating host-cell functions using hundreds of effector proteins delivered by its Dot/Icm secretion system(1). Among these, members of the SidE family (SidEs) regulate several cellular processes through a unique phosphoribosyl ubiquitination mechanism that bypasses the canonical ubiquitination machinery(2-4). The activity of SidEs is regulated by another Dot/Icm effector known as SidJ(5); however, the mechanism of this regulation is not completely understood(6,7). Here we demonstrate that SidJ inhibits the activity of SidEs by inducing the covalent attachment of glutamate moieties to SdeA-a member of the SidE family-at E860, one of the catalytic residues that is required for the mono-ADP-ribosyltransferase activity involved in ubiquitin activation(2). This inhibition by SidJ is spatially restricted in host cells because its activity requires the eukaryote-specific protein calmodulin (CaM). We solved a structure of SidJ-CaM in complex with AMP and found that the ATP used in this reaction is cleaved at the a-phosphate position by SidJ, which-in the absence of glutamate or modifiable SdeA-undergoes self-AMPylation. Our results reveal a mechanism of regulation in bacterial pathogenicity in which a glutamylation reaction that inhibits the activity of virulence factors is activated by host-factor-dependent acyl-adenylation.

【 授权许可】

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