Advances in development of new tools for the study of phosphohistidine

Makwana, Mehul V.; Muimo, Richmond; Jackson, Richard F. W.

doi:10.1038/labinvest.2017.126

Cited by 39 publications

(37 citation statements)

References 118 publications

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“…Therefore, synthetic pTyr mimics are the only option and have so far been incorporated into peptides or by genetic code expansion. However, these two approaches are both highly undeveloped to be utilized in full-length proteins (36). Overall, with the identification of Y60 and Y137 as necessary for inflammasome function, we have shed more light on how the adaptor protein is regulated by tyrosine phosphorylation in inflammasome complex formation.…”

Section: Discussionmentioning

confidence: 99%

Tyrosine Dephosphorylation of ASC Modulates the Activation of the NLRP3 and AIM2 Inflammasomes

et al. 2019

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The inflammasome is an intracellular multi-protein complex that orchestrates the release of the pro-inflammatory cytokines IL-1β and IL-18, and a form of cell death known as pyroptosis. Tyrosine phosphorylation of the inflammasome sensors NLRP3, AIM2, NLRC4, and the adaptor protein, apoptosis-associated speck-like protein (ASC) has previously been demonstrated to be essential in the regulation of the inflammasome. By using the pharmacological protein tyrosine phosphatase (PTPase) inhibitor, phenylarsine oxide (PAO), we have demonstrated that tyrosine dephosphorylation is an essential step for the activation of the NLRP3 and AIM2 inflammasomes in human and murine macrophages. We have also shown that PTPase activity is required for ASC nucleation leading to caspase-1 activation, IL-1β, and IL-18 processing and release, and cell death. Furthermore, by site-directed mutagenesis of ASC tyrosine residues, we have identified the phosphorylation of tyrosine Y60 and Y137 of ASC as critical for inflammasome assembly and function. Therefore, we report that ASC tyrosine dephosphorylation and phosphorylation are crucial events for inflammasome activation.

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Section: Discussionmentioning

confidence: 99%

Tyrosine Dephosphorylation of ASC Modulates the Activation of the NLRP3 and AIM2 Inflammasomes

et al. 2019

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“…To detect phosphorylated NPr, we used antibodies against phosphohistidine. Histidine can be phosphorylated on either of the two nitrogen atoms of its imidazole ring, forming phosphoramidates called πphosphohistidine (π-pHis) and τ-phosphohistidine (τ-pHis) ( Figure 3) (23,24,26). Based on Western blots with two different antibodies that are specific to the two phosphohistidine isomers, NPr-P consists primarily of π-pHis ( Figure 3).…”

Section: Sixa Dephosphorylates Npr-p In Vitro and Forms A Transient Pmentioning

confidence: 99%

“…Technical challenges have historically been a major obstacle in studying histidine phosphorylation (16)(17)(18), and recent studies suggest that this protein modification may be far more prevalent than has been previously appreciated (19)(20)(21)(22). In contrast to the very stable phosphoesters of serine, threonine, and tyrosine, which depend on phosphatases for dephosphorylation, the phosphoramidate of phosphohistidine can be quite labile (23)(24)(25)(26). For this reason, phosphohistidine phosphatases* may not be required for dephosphorylating phosphohistidine in vivo in many contexts.…”

Section: Introductionmentioning

confidence: 99%

The phosphohistidine phosphatase SixA dephosphorylates the phosphocarrier NPr

Schulte

Roggiani

Shi

et al. 2021

Journal of Biological Chemistry

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Histidine phosphorylation is a post-translational modification that alters protein function and also serves as an intermediate of phosphoryl transfer. Although phosphohistidine is relatively unstable, enzymatic dephosphorylation of this residue is apparently needed in some contexts, since both prokaryotic and eukaryotic phosphohistidine phosphatases have been reported. Here we identify the mechanism by which a bacterial phosphohistidine phosphatase dephosphorylates the nitrogen-related phosphotransferase system, a broadly conserved bacterial pathway that controls diverse metabolic processes. We show that the phosphatase SixA dephosphorylates the phosphocarrier protein NPr, and that the reaction proceeds through phosphoryl transfer from a histidine on NPr to a histidine on SixA. In addition, we show that Escherichia coli lacking SixA are out-competed by wild-type E. coli in the context of commensal colonization of the mouse intestine. Notably, this colonization defect requires NPr and is distinct from a previously identified in vitro growth defect associated with dysregulation of the nitrogen-related phosphotransferase system. The wide-spread conservation of SixA, and its coincidence with the phosphotransferase system studied here, suggests that this dephosphorylation mechanism may be conserved in other bacteria.

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“…Yet, over the last few years, several new tools have emerged and have led to a resurgence in the study of histidine phosphorylation, specifically thanks to the development of histidine phosphate analogs and pHis monoclonal antibodies [34][35][36][37]. In parallel, diverse methods were developed for the enrichment or detection of pHis using immunobinding [38][39][40][41][42][43], autoradiography [21,44], and NMR or mass spectrometry [22,[45][46][47][48][49].…”

Section: The Resurgence Of Histidine Phophorylationmentioning

confidence: 99%

NME/NM23/NDPK and Histidine Phosphorylation

Adam

Ning

Reina

et al. 2020

IJMS

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The NME (Non-metastatic) family members, also known as NDPKs (nucleoside diphosphate kinases), were originally identified and studied for their nucleoside diphosphate kinase activities. This family of kinases is extremely well conserved through evolution, being found in prokaryotes and eukaryotes, but also diverges enough to create a range of complexity, with homologous members having distinct functions in cells. In addition to nucleoside diphosphate kinase activity, some family members are reported to possess protein-histidine kinase activity, which, because of the lability of phosphohistidine, has been difficult to study due to the experimental challenges and lack of molecular tools. However, over the past few years, new methods to investigate this unstable modification and histidine kinase activity have been reported and scientific interest in this area is growing rapidly. This review presents a global overview of our current knowledge of the NME family and histidine phosphorylation, highlighting the underappreciated protein-histidine kinase activity of NME family members, specifically in human cells. In parallel, information about the structural and functional aspects of the NME family, and the knowns and unknowns of histidine kinase involvement in cell signaling are summarized.

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Advances in development of new tools for the study of phosphohistidine

Cited by 39 publications

References 118 publications

Tyrosine Dephosphorylation of ASC Modulates the Activation of the NLRP3 and AIM2 Inflammasomes

Tyrosine Dephosphorylation of ASC Modulates the Activation of the NLRP3 and AIM2 Inflammasomes

The phosphohistidine phosphatase SixA dephosphorylates the phosphocarrier NPr

NME/NM23/NDPK and Histidine Phosphorylation

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