Adenylate Cyclases of
            <i>Trypanosoma brucei</i>
            Inhibit the Innate Immune Response of the Host

Salmon, Didier; Vanwalleghem, Gilles; Morias, Yannick; Denoeud, Julie N.O.; Krumbholz, Carsten; Lhommé, Frédéric; Bachmaier, Sabine; Kador, Markus; Gossmann, Jasmin A; Dias, Fernando Braga Stehling; Muylder, Géraldine De; Uzureau, Pierrick; Magez, Stefan; Moser, Muriel; Baetseĺier, Patrick De; Abbeele, Jan Van Den; Beck, Alain; Boshart, Michael; Pays, Étienne

doi:10.1126/science.1222753

Cited by 124 publications

(177 citation statements)

References 41 publications

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“…These genes are often termed GRESAGs (gene related to ESAGs) (Pays et al, 2001). Although positioned outside vsg expression sites, GRESAGs can also be functional; members of the ESAG4 family have a function in both cytokinesis and early establishment of trypanosome infections in the mammalian host, for example (Salmon et al, 2012a;Salmon et al, 2012b).…”

Section: Introductionmentioning

confidence: 99%

A short bifunctional element operates to positively or negatively regulateESAG9expression in different developmental forms ofTrypanosoma brucei

Monk

Simmonds

Matthews

2013

Journal of Cell Science

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SummaryIn their mammalian host trypanosomes generate 'stumpy' forms from proliferative 'slender' forms as an adaptation for transmission to their tsetse fly vector. This transition is characterised by the repression of many genes while quiescent stumpy forms accumulate during each wave of parasitaemia. However, a subset of genes are upregulated either as an adaptation for transmission or to sustain infection chronicity. Among this group are ESAG9 proteins, whose genes were originally identified as a component of some telomeric variant surface glycoprotein gene expression sites, although many members of this diverse family are also transcribed elsewhere in the genome. ESAG9 genes are among the most highly regulated genes in transmissible stumpy forms, encoding a group of secreted proteins of cryptic function. To understand their developmental silencing in slender forms and activation in stumpy forms, the post-transcriptional control signals for a well conserved ESAG9 gene have been mapped. This identified a precise RNA sequence element of 34 nucleotides that contributes to gene expression silencing in slender forms but also acts positively, activating gene expression in stumpy forms. We predict that this bifunctional RNA sequence element is targeted by competing negative and positive regulatory factors in distinct developmental forms of the parasite. Analysis of the 39UTR regulatory regions flanking the highly diverse ESAG9 family reveals that the linear regulatory sequence is not highly conserved, suggesting that RNA structure is important for interactions with regulatory proteins.

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Section: Introductionmentioning

confidence: 99%

A short bifunctional element operates to positively or negatively regulateESAG9expression in different developmental forms ofTrypanosoma brucei

Monk

Simmonds

Matthews

2013

Journal of Cell Science

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“…Although studies on axonemal and luminal proteins predominated originally, considerable work has been done more recently on proteins of the trypanosome flagellar membrane (5). One of the first such proteins identified was a receptor type adenylate cyclase (6) that is likely involved in sensing the extracellular environment and relaying signals via synthesis of cAMP, and recent work on this family of proteins has uncovered roles for evasion of host innate immunity (7) and in social motility in insect stage procyclic forms (PFs) (8 -10). Furthermore, a variety of putative transporters and channels are present in the flagellar membrane (5), where they may play roles in nutrient or ion uptake and potentially in nutrient or solute sensing (11).…”

mentioning

confidence: 99%

KHARON Is an Essential Cytoskeletal Protein Involved in the Trafficking of Flagellar Membrane Proteins and Cell Division in African Trypanosomes

Sánchez

Tran

Valli

et al. 2016

Journal of Biological Chemistry

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African trypanosomes and related kinetoplastid parasites selectively traffic specific membrane proteins to the flagellar membrane, but the mechanisms for this trafficking are poorly understood. We show here that KHARON, a protein originally identified in Leishmania parasites, interacts with a putative trypanosome calcium channel and is required for its targeting to the flagellar membrane. KHARON is located at the base of the flagellar axoneme, where it likely mediates targeting of flagellar membrane proteins, but is also on the subpellicular microtubules and the mitotic spindle. Hence, KHARON is probably a multifunctional protein that associates with several components of the trypanosome cytoskeleton. RNA interference-mediated knockdown of KHARON mRNA results in failure of the calcium channel to enter the flagellar membrane, detachment of the flagellum from the cell body, and disruption of mitotic spindles. Furthermore, knockdown of KHARON mRNA induces a lethal failure of cytokinesis in both bloodstream (mammalian host) and procyclic (insect vector) life cycle stages, and KHARON is thus critical for parasite viability.

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“…AC is regulated by various molecules including bicarbonate (10), calcium (11), and hormones (12). Although cAMP is found in the trypanosomatid parasite Leishmania, little is known about its function (13,14).…”

mentioning

confidence: 99%

Globin-coupled heme containing oxygen sensor soluble adenylate cyclase in Leishmania prevents cell death during hypoxia

Santara

Roy

Mukherjee

et al. 2013

Proc. Natl. Acad. Sci. U.S.A.

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Significance Heme protein sensors interact with various gaseous molecules, such as CO, NO, or O 2 , and play a crucial role in transcriptional and regulatory events. In general, the sensory domains of heme proteins control signal transduction domains such as histidine kinases, phosphodiesterases, DNA-binding domains, guanylate cyclases, diguanylate cyclase, and aerotaxis transducers. Here we report globin-coupled heme containing adenylate cyclase from Leishmania major (HemAC-Lm), which regulates O 2 -dependent cAMP synthesis. Oxygen binding at heme iron of HemAC-Lm presumably triggers a conformational change in the sensor domain that sequentially stimulates the catalytic activity of the adenylate cyclase domain, resulting in the synthesis of the second messenger cAMP. This O 2 -dependent cAMP signaling is likely to function in cellular adaptability during hypoxia.

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Adenylate Cyclases of Trypanosoma brucei Inhibit the Innate Immune Response of the Host

Cited by 124 publications

References 41 publications

A short bifunctional element operates to positively or negatively regulateESAG9expression in different developmental forms ofTrypanosoma brucei

A short bifunctional element operates to positively or negatively regulateESAG9expression in different developmental forms ofTrypanosoma brucei

KHARON Is an Essential Cytoskeletal Protein Involved in the Trafficking of Flagellar Membrane Proteins and Cell Division in African Trypanosomes

Globin-coupled heme containing oxygen sensor soluble adenylate cyclase in Leishmania prevents cell death during hypoxia

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