Legionella pneumophila evades host-autophagic clearance using phosphoribosyl-polyubiquitin chains

Check for updatesLegionella pneumophila, the causative agent of Legionnaires' disease, colonises host cells through effective avoidance of host defense mechanisms.In this commentary, we highlight two recent Nature Communications studies reporting that two Legionella effectors, Sdc and Sde, working together to decorate the Legionella-containing vacuole (LCV) with unusual mixed ubiquitin chains.The phosphoribosyl modifications on the polyubiquitin chains block recognition by ubiquitin adaptors, thereby preventing the recruitment of host autophagy receptors like p62 to the LCV.This allows Legionella to evade autophagic clearance and establish a replicative niche within host cells. Legionella pneumophila catalyzes unusual phosphoribosylserine ubiquitinationThe SidE family of effector proteins (SidEs) from Legionella pneumophila catalyze a novel form of ubiquitination independent of the canonical E1-E2-E3 enzyme cascade 1,2 .First, the mono-ADPribosyltransferase (mART) domain of SidEs catalyzes the transfer of ADP-ribose from NAD + to arginine 42 of ubiquitin, generating ADPribosylated ubiquitin (ADPR-Ub).The phosphodiesterase (PDE) domain then processes ADPR-Ub to phosphoribosylated ubiquitin (PR-Ub) by cleaving the pyrophosphate bond and releasing AMP.The PDE domain then catalyzes the conjugation of PR-Ub to serine residues in substrate proteins via a phosphodiester bond.This occurs through a two-step mechanism: first, PR-Ub is linked to a catalytic histidine in the PDE domain via a phosphoamidate linkage, forming a covalent intermediate.Secondly, the phosphoribosyl-ubiquitin is transferred from the catalytic histidine to a serine hydroxyl in the substrate protein [3][4][5] .The activity of the SidE effectors is tightly regulated by other Legionella effectors.SidJ, a metaeffector, inhibits SidE-mediated PRubiquitination by glutamylating the mART domain catalytic residue E860, thereby blocking the initial step of ADPR-Ub generation.SidJ glutamylation activity requires the eukaryotic co-factor calmodulin and is activated by decreased cytosolic Ca 2+ levels [6][7][8] .Additionally, DupA and DupB, two Legionella effectors with PDE domains homologous to SidEs, act as specific deubiquitinases that reverse PR-serine ubiquitination 9,10 .Despite the structural similarity, DupA/B exhibit higher affinity for PRubiquitinated substrates compared to SidEs.This enables DupA/B to specifically cleave the phosphodiester bond between PR-Ub and serine residues, counteracting SidE activity.The balance between SidEmediated PR-ubiquitination and DupA/B-mediated deubiquitination dynamically regulates the extent and duration of this unique posttranslational modification during Legionella infection.