Bacterial virulence mediated by orthogonal post-translational modification

Chambers, Kaitlin A.; Scheck, Rebecca A.

doi:10.1038/s41589-020-0638-2

Cited by 26 publications

(19 citation statements)

References 102 publications

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“…324 In some bacterial infections, pathogenic phospholyases convert endogenous phosphoryl groups in host proteins to dehydrobutyrine units (via βelimination). 351 The resulting α,β-unsaturated carbonyl groups can deactivate key host proteins, modulating host metabolism and immune responses. 351 The complete inventory of such modifications, along with their downstream effects, remains unknown.…”

Section: Phospha-michael Additionmentioning

confidence: 99%

Bioorthogonal Reactions of Triarylphosphines and Related Analogues

2021

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Bioorthogonal phosphines were introduced in the context of the Staudinger ligation over 20 years ago. Since that time, phosphine probes have been used in myriad applications to tag azide-functionalized biomolecules. The Staudinger ligation also paved the way for the development of other phosphorus-based chemistries, many of which are widely employed in biological experiments. Several reviews have highlighted early achievements in the design and application of bioorthogonal phosphines. This review summarizes more recent advances in the field. We discuss innovations in classic Staudinger-like transformations that have enabled new biological pursuits. We also highlight relative newcomers to the bioorthogonal stage, including the cyclopropenone-phosphine ligation and the phospha-Michael reaction. The review concludes with chemoselective reactions involving phosphite and phosphonite ligations. For each transformation, we describe the overall mechanism and scope. We also showcase efforts to fine-tune the reagents for specific functions. We further describe recent applications of the chemistries in biological settings. Collectively, these examples underscore the versatility and breadth of bioorthogonal phosphine reagents.

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Section: Phospha-michael Additionmentioning

confidence: 99%

Bioorthogonal Reactions of Triarylphosphines and Related Analogues

2021

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“…[20][21][22] Manipulation of these processes largely results from either enzymatic post-translational modification of host targets or misregulation of specific host cell GTPases by L. pneumophila proteins. 23 Loss of individual translocated proteins rarely has negative consequences on intracellular growth, indicating that the system is built with multifold parallel biochemical strategies to ensure intracellular replication. 24 The importance of coordinating this complex system is emphasized by the central role in disease of the T4SS, which in its most dramatic form results in Legionnaire's disease, a potentially lethal pneumonia resulting from growth in alveolar macrophages after inhalation of water supplies bearing Legionella-laden amoebae.…”

Section: Introductionmentioning

confidence: 99%

“…There has been considerable work exploring the determinants of acceptor protein recognition by Sde family proteins, as pR-Ub modification proceeds via a previously uncharacterized pathway distinct from the canonical eukaryotic ubiquitination that results in an isopeptide bond linkage between Ub and an acceptor protein lysine. 23,40 Analysis of model target peptides and crystal structures of Sde family ART-NP regions have argued that target recognition by the Sde family involves presentation of a Ser residue in unstructured regions of acceptor proteins, 32,[37][38][39] enabling phosphoribosyl-linked ubiquitination of these cellular targets. This has led to the concept that Sde proteins are Serspecific pR-Ub transferases.…”

Section: Introductionmentioning

confidence: 99%

Members of the Legionella pneumophila Sde family target tyrosine residues for phosphoribosyl-linked ubiquitination

et al. 2021

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“…[20][21][22] Manipulation of these processes largely results from either enzymatic posttranslational modification of host targets or misregulation of specific host cell GTPases by L. pneumophia proteins. 23 Loss of individual translocated proteins rarely has negative consequences on intracellular growth, indicating that the system is built with multifold parallel biochemical strategies to ensure intracellular replication. 24 The importance of coordinating this complex system is emphasized by the central role in disease of the T4SS, which in its most dramatic form results in Legionnaire's disease, a potentially lethal pneumonia resulting from growth in alveolar macrophages after inhalation of water supplies bearing Legionella-laden ameobae.…”

Section: Introductionmentioning

confidence: 99%

“…There has been considerable work exploring the determinants of acceptor protein recognition by Sde family proteins, as pR-Ub modification proceeds via a previously uncharacterized pathway distinct from canonical eukaryotic ubiquitination that results in an isopeptide bond linkage between Ub and an acceptor protein lysine. 23,40 Analysis of model target peptides and crystal structures of the Sde family ART-NP regions have argued that target recognition by the Sde family involves presentation of a Ser residue in unstructured regions of acceptor proteins, 32,[37][38][39] enabling phosphoribosyl-linked ubiquitination of these cellular targets. This has led to the concept that Sde proteins are Ser-specific pR-Ub transferases.…”

Section: Introductionmentioning

confidence: 99%

Members of theLegionella pneumophilaSde Family Target Tyrosine Residues for Phosphoribosyl-Linked Ubiquitination

Zhang

McEwen

Sjoblom

et al. 2021

Preprint

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Legionella pneumophila establishes a replication vacuole by translocating hundreds of protein effectors through a type IV secretion system (T4SS). Among these translocated effectors are members of the Sde family, which catalyze phosphoribosyl-linked ubiquitination (pR-Ub) of host targets. Previous work has posited that Sde proteins solely target serine (Ser) residues within acceptor protein substrates. We show here that SdeC-mediated pR-Ub modification results from a stepwise reaction that also modifies tyrosine (Tyr) residues. Unexpectedly, the presence of an HA tag on Ub resulted in poly-pR-ubiquitination, consistent with the HA tag acting as an acceptor target. Interrogation of phosphoribosyl-linked HA-Ub revealed that Tyr4 was the preferred targeted residue, based on LC-MS/MS analysis of the crosslinked product. Further analysis using synthetic HA variants revealed promiscuous modification of Tyr, as crosslinking was prevented only by constructing a triple mutant in which all three Tyr within the HA sequence were substituted with Phe. Although previous work has indicated that Ser is the sole acceptor residue, we found no evidence of Ser preference over Tyr using Tyr->Ser replacement mutants. This work demonstrates that pR-ubiquitination by the Sde family is not limited to Ser-modification as previously proposed, and broadens the potential sites targeted by this family.

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Bacterial virulence mediated by orthogonal post-translational modification

Cited by 26 publications

References 102 publications

Bioorthogonal Reactions of Triarylphosphines and Related Analogues

Bioorthogonal Reactions of Triarylphosphines and Related Analogues

Members of the Legionella pneumophila Sde family target tyrosine residues for phosphoribosyl-linked ubiquitination

Members of theLegionella pneumophilaSde Family Target Tyrosine Residues for Phosphoribosyl-Linked Ubiquitination

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