Identification of novel cyclic nucleotide binding proteins in Trypanosoma cruzi

Jäger, Adriana V.; Gaudenzi, Javier G. De; Mild, Jesica Gabriela; Cormack, Bárbara Andrea Mc; Pantano, Sergio; Altschuler, Daniel L.; Edreira, Martín M.

doi:10.1016/j.molbiopara.2015.02.002

Cited by 21 publications

(25 citation statements)

References 37 publications

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“…While CARP1 contains a predicted cyclic-nucleotide binding domain, CARP2 and CARP4 are hypothetical conserved proteins associated with the eukaryotic flagellar proteome [ 118 , 119 , 120 ], and CARP3 is a hypothetical protein, kinetoplastid specific, such as CARP1. Experimental evidence confirmed that the T. cruzi CARP1 orthologue was capable of binding cAMP in vitro, validating the observation that CARP1 may be involved as genuine cAMP effector in T. brucei [ 37 ]. Although it is clear that cAMP can play a major role in the development of trypanosomes, how it controls or participates in the cell cycle and/or differentiation is presently unclear.…”

Section: T Brucei Camp Signaling Pathway: Fromsupporting

confidence: 70%

“…Moreover, in trypanosomes no classical cAMP effectors such as CNG channels or Epac have been characterized and there is no evidence for cAMP secretion via membrane channels. Conversely, a novel PKA-independent cAMP pathway involving several cAMP response proteins (CARPs) of unknown function, some of which are kinetoplastid-specific, was recently characterized in both T. brucei and T. cruzi [ 36 , 37 ].…”

Section: Introductionmentioning

confidence: 99%

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Adenylate Cyclases of Trypanosoma brucei, Environmental Sensors and Controllers of Host Innate Immune Response

Salmon

2018

Pathogens

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Trypanosoma brucei, etiological agent of Sleeping Sickness in Africa, is the prototype of African trypanosomes, protozoan extracellular flagellate parasites transmitted by saliva (Salivaria). In these parasites the molecular controls of the cell cycle and environmental sensing are elaborate and concentrated at the flagellum. Genomic analyses suggest that these parasites appear to differ considerably from the host in signaling mechanisms, with the exception of receptor-type adenylate cyclases (AC) that are topologically similar to receptor-type guanylate cyclase (GC) of higher eukaryotes but control a new class of cAMP targets of unknown function, the cAMP response proteins (CARPs), rather than the classical protein kinase A cAMP effector (PKA). T. brucei possesses a large polymorphic family of ACs, mainly associated with the flagellar membrane, and these are involved in inhibition of the innate immune response of the host prior to the massive release of immunomodulatory factors at the first peak of parasitemia. Recent evidence suggests that in T. brucei several insect-specific AC isoforms are involved in social motility, whereas only a few AC isoforms are involved in cytokinesis control of bloodstream forms, attesting that a complex signaling pathway is required for environmental sensing. In this review, after a general update on cAMP signaling pathway and the multiple roles of cAMP, I summarize the existing knowledge of the mechanisms by which pathogenic microorganisms modulate cAMP levels to escape immune defense.

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Section: T Brucei Camp Signaling Pathway: Fromsupporting

confidence: 70%

Section: Introductionmentioning

confidence: 99%

Adenylate Cyclases of Trypanosoma brucei, Environmental Sensors and Controllers of Host Innate Immune Response

Salmon

2018

Pathogens

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“…We have previously identified a number of potential cAMP response proteins (CARPs) by genome-wide RNAi library screening in T. brucei 29 . CARP1 has three CNB domains and the T. cruzi ortholog 60 binds cAMP. Interestingly, CARP1 is exclusively found in kinetoplastid genomes and possibly coevolved with the ligand swap of PKA away from cAMP.…”

Section: Discussionmentioning

confidence: 99%

Nucleoside analogue activators of cyclic AMP-independent protein kinase A of Trypanosoma

et al. 2019

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Protein kinase A (PKA), the main effector of cAMP in eukaryotes, is a paradigm for the mechanisms of ligand-dependent and allosteric regulation in signalling. Here we report the orthologous but cAMP-independent PKA of the protozoan Trypanosoma and identify 7-deaza-nucleosides as potent activators (EC 50 ≥ 6.5 nM) and high affinity ligands ( K D ≥ 8 nM). A co-crystal structure of trypanosome PKA with 7-cyano-7-deazainosine and molecular docking show how substitution of key amino acids in both CNB domains of the regulatory subunit and its unique C-terminal αD helix account for this ligand swap between trypanosome PKA and canonical cAMP-dependent PKAs. We propose nucleoside-related endogenous activators of Trypanosoma brucei PKA (TbPKA). The existence of eukaryotic CNB domains not associated with binding of cyclic nucleotides suggests that orphan CNB domains in other eukaryotes may bind undiscovered signalling molecules. Phosphoproteome analysis validates 7-cyano-7-deazainosine as powerful cell-permeable inducer to explore cAMP-independent PKA signalling in medically important neglected pathogens.

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“…One of the genes knocked down in the CpdA-resistant cultures was Tb427tmp.01.7890 ( CARP1 ; Tb927.11.16210 in T. b. brucei reference strain TREU 927), encoding a 705-amino-acid protein containing two apparently intact and one partial cyclic AMP binding-like domain, that is conserved in synteny in each of the kinetoplastid genomes sequenced. Recently, the homolog of CARP1 in T. cruzi TcCLB.508523.80 has been reported to bind cyclic nucleotides, using cAMP and cGMP displacement assays ( Jäger et al, 2014 ), further validating the role of CARP1 as a downstream cAMP signaling effector. CARP2–4 are proteins of as yet unknown functions but some of them have a probable flagellar localization, consistent with a role in mediating or regulating a cAMP signal ( Gould et al, 2013 ).…”

Section: Novel Downstream Effectors Of Camp In Trypanosomesmentioning

confidence: 91%

The ever unfolding story of cAMP signaling in trypanosomatids: vive la difference!

2015

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Kinetoplastids are unicellular, eukaryotic, flagellated protozoans containing the eponymous kinetoplast. Within this order, the family of trypanosomatids are responsible for some of the most serious human diseases, including Chagas disease (Trypanosoma cruzi), sleeping sickness (Trypanosoma brucei spp.), and leishmaniasis (Leishmania spp). Although cAMP is produced during the life cycle stages of these parasites, its signaling pathways are very different from those of mammals. The absence of G-protein-coupled receptors, the presence of structurally different adenylyl cyclases, the paucity of known cAMP effector proteins and the stringent need for regulation of cAMP in the small kinetoplastid cells all suggest a significantly different biochemical pathway and likely cell biology. However, each of the main kinetoplastid parasites express four class 1-type cyclic nucleotide-specific phosphodiesterases (PDEA-D), which have highly similar catalytic domains to that of human PDEs. To date, only TbrPDEB, expressed as two slightly different isoforms TbrPDEB1 and B2, has been found to be essential when ablated. Although the genomes contain reasonably well conserved genes for catalytic and regulatory domains of protein kinase A, these have been shown to have varied structural and functional roles in the different species. Recent discovery of a role of cAMP/AMP metabolism in a quorum-sensing signaling pathway in T. brucei, and the identification of downstream cAMP Response Proteins (CARPs) whose expression levels correlate with sensitivity to PDE inhibitors, suggests a complex signaling cascade. The interplay between the roles of these novel CARPs and the quorum-sensing signaling pathway on cell division and differentiation makes for intriguing cell biology and a new paradigm in cAMP signal transduction, as well as potential targets for trypanosomatid-specific cAMP pathway-based therapeutics.

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Identification of novel cyclic nucleotide binding proteins in Trypanosoma cruzi

Cited by 21 publications

References 37 publications

Adenylate Cyclases of Trypanosoma brucei, Environmental Sensors and Controllers of Host Innate Immune Response

Adenylate Cyclases of Trypanosoma brucei, Environmental Sensors and Controllers of Host Innate Immune Response

Nucleoside analogue activators of cyclic AMP-independent protein kinase A of Trypanosoma

The ever unfolding story of cAMP signaling in trypanosomatids: vive la difference!

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