Uropygial gland size and composition varies according to experimentally modified microbiome in Great tits

International audienceBackground: Parasites exert important selective pressures on host life history traits. In birds, feathers are inhabited by numerous microorganisms, some of them being able to degrade feathers or lead to infections. Preening feathers with secretions of the uropygial gland has been found to act as an antimicrobial defence mechanism, expected to regulate feather microbial communities and thus limit feather abrasion and infections. Here, we used an experimental approach to test whether Great tits (Parus major) modify their investment in the uropygial gland in response to differences in environmental microorganisms.Results: We found that males, but not females, modified the size of their gland when exposed to higher bacterial densities on feathers. We also identified 16 wax esters in the uropygial gland secretions. The relative abundance of some of these esters changed in males and females, while the relative abundance of others changed only in females when exposed to greater bacterial loads on feathers.Conclusion: Birds live in a bacterial world composed of commensal and pathogenic microorganisms. This study provides the first experimental evidence for modifications of investment in the defensive trait that is the uropygial gland in response to environmental microorganisms in a wild bird

Mutation in human CLPX elevates levels of δ-aminolevulinate synthase and protoporphyrin IX to promote erythropoietic protoporphyria

Loss-of-function mutations in genes for heme biosynthetic enzymes can give rise to congenital porphyrias, eight forms of which have been described. The genetic penetrance of the porphyrias is clinically variable, underscoring the role of additional causative, contributing, and modifier genes. We previously discovered that the mitochondrial AAA+ unfoldase ClpX promotes heme biosynthesis by activation of δ-aminolevulinate synthase (ALAS), which catalyzes the first step of heme synthesis. CLPX has also been reported to mediate heme-induced turnover of ALAS. Here we report a dominant mutation in the ATPase active site of human CLPX, p.Gly298Asp, that results in pathological accumulation of the heme biosynthesis intermediate protoporphyrin IX (PPIX). Amassing of PPIX in erythroid cells promotes erythropoietic protoporphyria (EPP) in the affected family. The mutation in CLPX inactivates its ATPase activity, resulting in coassembly of mutant and WT protomers to form an enzyme with reduced activity. The presence of low-activity CLPX increases the posttranslational stability of ALAS, causing increased ALAS protein and ALA levels, leading to abnormal accumulation of PPIX. Our results thus identify an additional molecular mechanism underlying the development of EPP and further our understanding of the multiple mechanisms by which CLPX controls heme metabolism. Keywords: heme biosynthesis; porphyria; ALAS; protein unfoldases; AAA+ ATPaseNational Institutes of Health (U.S.) (Grant F32 DK095726)National Institutes of Health (U.S.) (Grant R01 GM049224

Identification de(s) gène(s) et des mécanismes pathogéniques responsables d'une nouvelle forme de Protoporphyrie Erythropoïétique Humaine

La protoporphyrie érythropoïétique (PPE) est une maladie métabolique héréditaire rare résultant d un déficit en ferrochélatase (FECH), dernière enzyme de la voie de biosynthèse de l hème. Ce déficit entraîne l accumulation anormale de protoporphyrine IX (PP) libre, produit phototoxique déclenchant chez le patient une photodermatose algique et rarement des incidents hépatiques graves. Le mode de transmission original de cette maladie repose sur la cotransmission d une mutation FECH délétère et de l allèle FECH hypomorphe IVS3-48C, présent dans la population générale. Quatre familles atypiques sans atteinte FECH ont été identifiées, suggérant l existence d un variant de PPE. Les objectifs de cette thèse ont donc été d affiner la description clinique du phénotype de ces patients, d identifier l anomalie moléculaire et de comprendre le mécanisme physiopathologique responsable de l accumulation de PP. Cette thèse a permis : -1) d identifier des mutations activatrices de l acide -aminolévulinique synthase isoforme érythroïde spécifique (ALAS2), responsables d une surproduction d acide -aminolévulinique (ALA). La FECH, bien que fonctionnelle, devient limitante, entraînant l accumulation de PP libre et PP complexée au zinc. Les mutations responsables de protoporphyrie érythropoïétique dominante liée à l X (XLDPP) sont limitées à un domaine défini du domaine C-terminal de l ALAS2 causant sa délétion ou son remplacement, ce qui permet une libération plus rapide de l ALA. - 2) de démontrer l existence d un troisième variant de PPE/XLDPP. Une analyse de liaison pan génomique couplée à un séquençage exomique du cas index a permis de restreindre la liste des gènes candidatsPARIS-BIUSJ-Biologie recherche (751052107) / SudocSudocFranceF

Preen secretions encode information on MHC similarity in certain sex-dyads in a monogamous seabird

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Jacob et al _ BMC _ Gland composition

Data of chemical compounds contained in the grand (see Table S1 for identification

Human Erythroid 5-Aminolevulinate Synthase Mutations Associated with X-Linked Protoporphyria Disrupt the Conformational Equilibrium and Enhance Product Release

Regulation of 5-aminolevulinate synthase (ALAS) is at the origin of balanced heme production in mammals. Mutations in the C-terminal region of human erythroid-specific ALAS (hALAS2) are associated with X-linked protoporphyria (XLPP), a disease characterized by extreme photosensitivity, with elevated blood concentrations of free protoporphyrin IX and zinc protoporphyrin. To investigate the molecular basis for this disease, recombinant hALAS2 and variants of the enzyme harboring the gain-of-function XLPP mutations were constructed, purified, and analyzed kinetically, spectroscopically, and thermodynamically. Enhanced activities of the XLPP variants resulted from increases in the rate at which the product 5-aminolevulinate (ALA) was released from the enzyme. Circular dichroism spectroscopy revealed that the XLPP mutations altered the microenvironment of the pyridoxal 5′-phosphate cofactor, which underwent further and specific alterations upon succinyl-CoA binding. Transient kinetic analyses of the variant-catalyzed reactions and protein fluorescence quenching upon binding of ALA to the XLPP variants demonstrated that the protein conformational transition step associated with product release was predominantly affected. Of relevance is the fact that XLPP could also be modeled in cell culture. We propose that (1) the XLPP mutations destabilize the succinyl-CoA-induced hALAS2 closed conformation and thus accelerate ALA release, (2) the extended C-terminus of wild-type mammalian ALAS2 provides a regulatory role that allows for allosteric modulation of activity, thereby controlling the rate of erythroid heme biosynthesis, and (3) this control is disrupted in XLPP, resulting in porphyrin accumulation

Finely-tuned regulation of AMP-activated protein kinase is crucial for human adult erythropoiesis

International audienceAMP-activated protein kinase (AMPK) is a heterotrimeric complex containing α, β, and γ subunits involved in maintaining integrity and survival of murine red blood cells. Indeed, Ampk α1-/- , Ampk β1-/- and Ampk γ1-/- mice develop hemolytic anemia and the plasma membrane of their red blood cells shows elasticity defects. The membrane composition evolves continuously along erythropoiesis and during red blood cell maturation; defects due to the absence of Ampk could be initiated during erythropoiesis. We, therefore, studied the role of AMPK during human erythropoiesis. Our data show that AMPK activation had two distinct phases in primary erythroblasts. The phosphorylation of AMPK (Thr172) and its target acetyl CoA carboxylase (Ser79) was elevated in immature erythroblasts (glycophorin Alow), then decreased conjointly with erythroid differentiation. In erythroblasts, knockdown of the α1 catalytic subunit by short hairpin RNA led to a decrease in cell proliferation and alterations in the expression of membrane proteins (band 3 and glycophorin A) associated with an increase in phosphorylation of adducin (Ser726). AMPK activation in mature erythroblasts (glycophorin Ahigh), achieved through the use of direct activators (GSK621 and compound 991), induced cell cycle arrest in the S phase, the induction of autophagy and caspase-dependent apoptosis, whereas no such effects were observed in similarly treated immature erythroblasts. Thus, our work suggests that AMPK activation during the final stages of erythropoiesis is deleterious. As the use of direct AMPK activators is being considered as a treatment in several pathologies (diabetes, acute myeloid leukemia), this observation is pivotal. Our data highlighted the importance of the finely-tuned regulation of AMPK during human erythropoiesis