Polar auxin transport in the Arabidopsis (Arabidopsis thaliana) root tip maintains high auxin levels around the stem cell niche that gradually decrease in dividing cells but increase again once they transition toward differentiation. Protophloem differentiates earlier than other proximal tissues and employs a unique auxin "canalization" machinery that is thought to balance auxin efflux with retention. It consists of a proposed activator of PIN-FORMED (PIN) auxin efflux carriers, the cAMP-, cGMP- and Calcium-dependent (AGC) kinase PROTEIN KINASE ASSOCIATED WITH BRX (PAX); its inhibitor, BREVIS RADIX (BRX); and PHOSPHATIDYLINOSITOL-4-PHOSPHATE-5-KINASE (PIP5K) enzymes, which promote polar PAX and BRX localization. Because of a dynamic PAX-BRX-PIP5K interplay, the net cellular output of this machinery remains unclear. In this study, we deciphered the dosage-sensitive regulatory interactions among PAX, BRX, and PIP5K by their ectopic expression in developing xylem vessels. The data suggest that the dominant collective output of the PAX-BRX-PIP5K module is a localized reduction in PIN abundance. This requires PAX-stimulated clathrin-mediated PIN endocytosis upon site-specific phosphorylation, which distinguishes PAX from other AGC kinases. An ectopic assembly of the PAX-BRX-PIP5K module is sufficient to cause cellular auxin retention and affects root growth vigor by accelerating the trajectory of xylem vessel development. Our data thus provide direct evidence that local manipulation of auxin efflux alters the timing of cellular differentiation in the root.

• MeSH
• Arabidopsis * metabolismus   genetika   růst a vývoj   MeSH
• biologický transport MeSH
• fosfotransferasy s alkoholovou skupinou jako akceptorem metabolismus   genetika   MeSH
• kořeny rostlin metabolismus   růst a vývoj   genetika   MeSH
• kyseliny indoloctové * metabolismus   MeSH
• membránové transportní proteiny metabolismus   genetika   MeSH
• protein-serin-threoninkinasy * MeSH
• proteiny huseníčku * metabolismus   genetika   MeSH
• regulace genové exprese u rostlin MeSH
• xylém metabolismus   růst a vývoj   MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH
• Názvy látek
• AT1G66150 protein, Arabidopsis MeSH Prohlížeč
• BREVIS RADIX protein, Arabidopsis MeSH Prohlížeč
• fosfotransferasy s alkoholovou skupinou jako akceptorem MeSH
• kyseliny indoloctové * MeSH
• membránové transportní proteiny MeSH
• protein-serin-threoninkinasy * MeSH
• proteiny huseníčku * MeSH

An environmentally responsive root system is crucial for plant growth and crop yield, especially in suboptimal soil conditions. This responsiveness enables the plant to exploit regions of high nutrient density while simultaneously minimizing abiotic stress. Despite the vital importance of root systems in regulating plant growth, significant gaps of knowledge exist in the mechanisms that regulate their architecture. Auxin defines both the frequency of lateral root (LR) initiation and the rate of LR outgrowth. Here, we describe a search for proteins that regulate root system architecture (RSA) by interacting directly with a key auxin transporter, PIN1. The native separation of Arabidopsis plasma membrane protein complexes identified several PIN1 co-purifying proteins. Among them, AZG1 was subsequently confirmed as a PIN1 interactor. Here, we show that, in Arabidopsis, AZG1 is a cytokinin (CK) import protein that co-localizes with and stabilizes PIN1, linking auxin and CK transport streams. AZG1 expression in LR primordia is sensitive to NaCl, and the frequency of LRs is AZG1-dependent under salt stress. This report therefore identifies a potential point for auxin:cytokinin crosstalk, which shapes RSA in response to NaCl.

• Klíčová slova
• auxin, auxin transport, crosstalk, cytokinin, cytokinin transport, lateral root, salt stress,
• MeSH
• Arabidopsis * MeSH
• chlorid sodný MeSH
• cytokininy * metabolismus   MeSH
• kořeny rostlin metabolismus   MeSH
• kyseliny indoloctové metabolismus   MeSH
• membránové transportní proteiny * genetika   metabolismus   MeSH
• proteiny huseníčku * genetika   metabolismus   MeSH
• regulace genové exprese u rostlin MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH
• Názvy látek
• chlorid sodný MeSH
• cytokininy * MeSH
• kyseliny indoloctové MeSH
• membránové transportní proteiny * MeSH
• PIN1 protein, Arabidopsis MeSH Prohlížeč
• proteiny huseníčku * MeSH

About 15% of colorectal cancer (CRC) patients have first-degree relatives affected by the same malignancy. However, for most families the cause of familial aggregation of CRC is unknown. To identify novel high-to-moderate-penetrance germline variants underlying CRC susceptibility, we performed whole exome sequencing (WES) on four CRC cases and two unaffected members of a Polish family without any mutation in known CRC predisposition genes. After WES, we used our in-house developed Familial Cancer Variant Prioritization Pipeline and identified two novel variants in the solute carrier family 15 member 4 (SLC15A4) gene. The heterozygous missense variant, p. Y444C, was predicted to affect the phylogenetically conserved PTR2/POT domain and to have a deleterious effect on the function of the encoded peptide/histidine transporter. The other variant was located in the upstream region of the same gene (GRCh37.p13, 12_129308531_C_T; 43 bp upstream of transcription start site, ENST00000266771.5) and it was annotated to affect the promoter region of SLC15A4 as well as binding sites of 17 different transcription factors. Our findings of two distinct variants in the same gene may indicate a synergistic up-regulation of SLC15A4 as the underlying genetic cause and implicate this gene for the first time in genetic inheritance of familial CRC.

• Klíčová slova
• Familial colorectal cancer, Germline variant, SLC15A4, Whole exome sequencing,
• MeSH
• genetická predispozice k nemoci MeSH
• kolorektální nádory * genetika   patologie   MeSH
• lidé MeSH
• membránové transportní proteiny genetika   MeSH
• proteiny nervové tkáně genetika   MeSH
• rodokmen MeSH
• sekvenování exomu MeSH
• zárodečné buňky patologie   MeSH
• zárodečné mutace * MeSH
• Check Tag
• lidé MeSH
• Publikační typ
• časopisecké články MeSH
• Názvy látek
• membránové transportní proteiny MeSH
• proteiny nervové tkáně MeSH
• SLC15A4 protein, human MeSH Prohlížeč

Much of plant development depends on cell-to-cell redistribution of the plant hormone auxin, which is facilitated by the plasma membrane (PM) localized PIN FORMED (PIN) proteins. Auxin export activity, developmental roles, subcellular trafficking, and polarity of PINs have been well studied, but their structure remains elusive besides a rough outline that they contain two groups of 5 alpha-helices connected by a large hydrophilic loop (HL). Here, we focus on the PIN1 HL as we could produce it in sufficient quantities for biochemical investigations to provide insights into its secondary structure. Circular dichroism (CD) studies revealed its nature as an intrinsically disordered protein (IDP), manifested by the increase of structure content upon thermal melting. Consistent with IDPs serving as interaction platforms, PIN1 loops homodimerize. PIN1 HL cytoplasmic overexpression in Arabidopsis disrupts early endocytic trafficking of PIN1 and PIN2 and causes defects in the cotyledon vasculature formation. In summary, we demonstrate that PIN1 HL has an intrinsically disordered nature, which must be considered to gain further structural insights. Some secondary structures may form transiently during pairing with known and yet-to-be-discovered interactors.

• Klíčová slova
• PIN1, dimerization, hydrophilic hoop, intrinsic disorder, subcellular trafficking,
• MeSH
• Arabidopsis * metabolismus   MeSH
• biologický transport MeSH
• kořeny rostlin metabolismus   MeSH
• kyseliny indoloctové metabolismus   MeSH
• membránové transportní proteiny genetika   metabolismus   MeSH
• proteiny huseníčku * genetika   metabolismus   MeSH
• vnitřně neuspořádané proteiny * genetika   metabolismus   MeSH
• Publikační typ
• časopisecké články MeSH
• Názvy látek
• kyseliny indoloctové MeSH
• membránové transportní proteiny MeSH
• PIN1 protein, Arabidopsis MeSH Prohlížeč
• proteiny huseníčku * MeSH
• vnitřně neuspořádané proteiny * MeSH

Loss of genome stability leads to reduced fitness, fertility and a high mutation rate. Therefore, the genome is guarded by the pathways monitoring its integrity and neutralizing DNA lesions. To analyze the mechanism of DNA damage induction by cytidine analog zebularine, we performed a forward-directed suppressor genetic screen in the background of Arabidopsis thaliana zebularine-hypersensitive structural maintenance of chromosomes 6b (smc6b) mutant. We show that smc6b hypersensitivity was suppressed by the mutations in EQUILIBRATIVE NUCLEOSIDE TRANSPORTER 3 (ENT3), DNA METHYLTRANSFERASE 1 (MET1) and DECREASE IN DNA METHYLATION 1 (DDM1). Superior resistance of ent3 plants to zebularine indicated that ENT3 is likely necessary for the import of the drug to the cells. Identification of MET1 and DDM1 suggested that zebularine induces DNA damage by interference with the maintenance of CG DNA methylation. The same holds for structurally similar compounds 5-azacytidine and 2-deoxy-5-azacytidine. Based on our genetic and biochemical data, we propose that zebularine induces enzymatic DNA-protein crosslinks (DPCs) of MET1 and zebularine-containing DNA in Arabidopsis, which was confirmed by native chromatin immunoprecipitation experiments. Moreover, zebularine-induced DPCs accumulate preferentially in 45S rDNA chromocenters in a DDM1-dependent manner. These findings open a new avenue for studying genome stability and DPC repair in plants.

• MeSH
• Arabidopsis MeSH
• cytidin analogy a deriváty   toxicita   MeSH
• DNA vazebné proteiny genetika   MeSH
• DNA-(cytosin-5-)methyltransferasa genetika   MeSH
• heterochromatin účinky léků   metabolismus   MeSH
• léková rezistence MeSH
• membránové transportní proteiny genetika   MeSH
• mutace MeSH
• mutageny toxicita   MeSH
• proteiny buněčného cyklu genetika   MeSH
• proteiny huseníčku genetika   MeSH
• RNA ribozomální účinky léků   genetika   MeSH
• transkripční faktory genetika   MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH
• Názvy látek
• AT4G05120 protein, Arabidopsis MeSH Prohlížeč
• cytidin MeSH
• DDM1 protein, Arabidopsis MeSH Prohlížeč
• DNA vazebné proteiny MeSH
• DNA-(cytosin-5-)methyltransferasa MeSH
• heterochromatin MeSH
• membránové transportní proteiny MeSH
• MET1 protein, Arabidopsis MeSH Prohlížeč
• mutageny MeSH
• proteiny buněčného cyklu MeSH
• proteiny huseníčku MeSH
• pyrimidin-2-one beta-ribofuranoside MeSH Prohlížeč
• RNA ribozomální MeSH
• RNA, ribosomal, 45S MeSH Prohlížeč
• SMC6B protein, Arabidopsis MeSH Prohlížeč
• transkripční faktory MeSH

Formation of mitochondria by the conversion of a bacterial endosymbiont was a key moment in the evolution of eukaryotes. It was made possible by outsourcing the endosymbiont's genetic control to the host nucleus, while developing the import machinery for proteins synthesized on cytosolic ribosomes. The original protein export machines of the nascent organelle remained to be repurposed or were completely abandoned. This review follows the evolutionary fates of three prokaryotic inner membrane translocases Sec, Tat, and YidC. Homologs of all three translocases can still be found in current mitochondria, but with different importance for mitochondrial function. Although the mitochondrial YidC homolog, Oxa1, became an omnipresent independent insertase, the other two remained only sporadically present in mitochondria. Only a single substrate is known for the mitochondrial Tat and no function has yet been assigned for the mitochondrial Sec. Finally, this review compares these ancestral mitochondrial proteins with their paralogs operating in the plastids and the endomembrane system.

• Klíčová slova
• eukaryogenesis, membrane trafficking, neofunctionalization, protein targeting,
• MeSH
• Eukaryota * genetika   metabolismus   MeSH
• membránové transportní proteiny genetika   metabolismus   MeSH
• mitochondriální proteiny genetika   metabolismus   MeSH
• mitochondrie genetika   metabolismus   MeSH
• molekulární evoluce MeSH
• proteiny z Escherichia coli * genetika   MeSH
• transport proteinů MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH
• přehledy MeSH
• Názvy látek
• membránové transportní proteiny MeSH
• mitochondriální proteiny MeSH
• proteiny z Escherichia coli * MeSH

Drug resistance has now become a serious concern in the domain of microbial infection. Bacteria are becoming smarter by displaying a variety of mechanisms during drug resistance. It is not only helping bacteria to adapt nicely in adverse environment but it also makes a smart system for better availability of nutritional status for microorganisms. In this domain, pathogenic bacteria are extensively studied and their mechanism for drug resistance is well explored. The common modes in bacterial resistance include degradation of antibiotics by enzymes, antibiotic target modification or inactivation by enzymatic actions, complete replacement of antibiotic targets, quorum sensing (QS) mechanism, and efflux pump-based extrusion of antibiotics. In this review, various mechanisms of drug resistance in bacteria have been highlighted with giving the importance of efflux pumps. This can be explored as a knowledge source for the management of a variety of bacterial infections, related disease and vibrant clue for next-generation drug development.

• MeSH
• antibakteriální látky * farmakologie   MeSH
• Bacteria * účinky léků   genetika   metabolismus   MeSH
• bakteriální proteiny genetika   metabolismus   MeSH
• léková rezistence * fyziologie   MeSH
• membránové transportní proteiny * genetika   metabolismus   MeSH
• Publikační typ
• časopisecké články MeSH
• přehledy MeSH
• Názvy látek
• antibakteriální látky * MeSH
• bakteriální proteiny MeSH
• membránové transportní proteiny * MeSH

Aluminium (Al) stress is a major limiting factor for worldwide crop production in acid soils. In Arabidopsis thaliana, the TAA1-dependent local auxin biosynthesis in the root-apex transition zone (TZ), the major perception site for Al toxicity, is crucial for the Al-induced root-growth inhibition, while the mechanism underlying Al-regulated auxin accumulation in the TZ is not fully understood. In the present study, the role of auxin transport in Al-induced local auxin accumulation in the TZ and root-growth inhibition was investigated. Our results showed that PIN-FORMED (PIN) proteins such as PIN1, PIN3, PIN4 and PIN7 and AUX1/LAX proteins such as AUX1, LAX1 and LAX2 were all ectopically up-regulated in the root-apex TZ in response to Al stress and coordinately regulated local auxin accumulation in the TZ and root-growth inhibition. The ectopic up-regulation of PIN1 in the TZ under Al stress was regulated by both ethylene and auxin, with auxin signalling acting downstream of ethylene. Al-induced PIN1 up-regulation and auxin accumulation in the root-apex TZ was also regulated by the calossin-like protein BIG. Together, our results provide insight into how Al stress induces local auxin accumulation in the TZ and root-growth inhibition through the local regulation of auxin transport.

• Klíčová slova
• PIN1, aluminium, auxin transport, root growth, root-apex transition zone,
• MeSH
• Arabidopsis účinky léků   genetika   růst a vývoj   fyziologie   MeSH
• biologický transport MeSH
• ethyleny metabolismus   MeSH
• fyziologický stres MeSH
• hliník toxicita   MeSH
• kořeny rostlin účinky léků   genetika   růst a vývoj   metabolismus   MeSH
• kyseliny indoloctové metabolismus   MeSH
• membránové transportní proteiny genetika   metabolismus   MeSH
• proteiny huseníčku genetika   metabolismus   MeSH
• proteiny vázající kalmodulin genetika   metabolismus   MeSH
• regulace genové exprese u rostlin MeSH
• regulátory růstu rostlin metabolismus   MeSH
• upregulace MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH
• Názvy látek
• BIG protein, Arabidopsis MeSH Prohlížeč
• ethylene MeSH Prohlížeč
• ethyleny MeSH
• hliník MeSH
• kyseliny indoloctové MeSH
• membránové transportní proteiny MeSH
• PIN1 protein, Arabidopsis MeSH Prohlížeč
• proteiny huseníčku MeSH
• proteiny vázající kalmodulin MeSH
• regulátory růstu rostlin MeSH

Polar subcellular localization of the PIN exporters of the phytohormone auxin is a key determinant of directional, intercellular auxin transport and thus a central topic of both plant cell and developmental biology. Arabidopsis mutants lacking PID, a kinase that phosphorylates PINs, or the MAB4/MEL proteins of unknown molecular function display PIN polarity defects and phenocopy pin mutants, but mechanistic insights into how these factors convey PIN polarity are missing. Here, by combining protein biochemistry with quantitative live-cell imaging, we demonstrate that PINs, MAB4/MELs, and AGC kinases interact in the same complex at the plasma membrane. MAB4/MELs are recruited to the plasma membrane by the PINs and in concert with the AGC kinases maintain PIN polarity through limiting lateral diffusion-based escape of PINs from the polar domain. The PIN-MAB4/MEL-PID protein complex has self-reinforcing properties thanks to positive feedback between AGC kinase-mediated PIN phosphorylation and MAB4/MEL recruitment. We thus uncover the molecular mechanism by which AGC kinases and MAB4/MEL proteins regulate PIN localization and plant development.

• Klíčová slova
• Arabidopsis, cell polarity, lateral diffusion, plant development, polar auxin transport, positive feedback, protein phosphorylation,
• MeSH
• Arabidopsis * genetika   metabolismus   MeSH
• biologický transport MeSH
• kořeny rostlin metabolismus   MeSH
• kyseliny indoloctové MeSH
• membránové transportní proteiny genetika   MeSH
• polarita buněk MeSH
• proteiny huseníčku * genetika   metabolismus   MeSH
• regulace genové exprese u rostlin MeSH
• rostlinné buňky metabolismus   MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH
• Názvy látek
• kyseliny indoloctové MeSH
• membránové transportní proteiny MeSH
• proteiny huseníčku * MeSH

OBJECTIVES: This study evaluated the implications of clinically acquired miltefosine resistance (MIL-R) by assessing virulence in mice and sand flies to reveal the potential of MIL-R strains to circulate. METHODS: Experimental infections with the MIL-R clinical Leishmania infantum isolate MHOM/FR/2005/LEM5159, having a defect in the LiROS3 subunit of the MIL-transporter, and its syngeneic experimentally reconstituted MIL-S counterpart (LEM5159LiROS3) were performed in BALB/c mice and Lutzomyia longipalpis and Phlebotomus perniciosus sand flies. In mice, the amastigote burdens in liver and spleen were compared microscopically using Giemsa smears and by bioluminescent imaging. During the sand fly infections, the percentage of infected flies, parasite load, colonization of the stomodeal valve and metacyclogenesis were evaluated. The stability of the MIL-R phenotype after sand fly and mouse passage was determined as well. RESULTS: The fitness of the MIL-R strain differed between the mouse and sand fly infection model. In mice, a clear fitness loss was observed compared to the LiROS3-reconstituted susceptible strain. This defect could be rescued by episomal reconstitution with a wildtype LiROS3 copy. However, this fitness loss was not apparent in the sand fly vector, resulting in metacyclogenesis and efficient colonization of the stomodeal valve. Resistance was stable after passage in both sand fly and mouse. CONCLUSION: The natural MIL-R strain is significantly hampered in its ability to multiply and cause a typical visceral infection pattern in BALB/c mice. However, this LiROS3-deficient strain efficiently produced mature infections and metacyclic promastigotes in the sand fly vector highlighting the transmission potential of this particular MIL-R clinical Leishmania strain.

• Klíčová slova
• Bioluminescent imaging, Fitness, Leishmania infantum, Lutzomyia longipalpis, Miltefosine-resistance, Phlebotomus perniciosus, Visceral leishmaniasis,
• MeSH
• antiprotozoální látky farmakologie   MeSH
• fosforylcholin analogy a deriváty   farmakologie   MeSH
• hmyz - vektory parazitologie   MeSH
• Leishmania infantum * účinky léků   genetika   patogenita   MeSH
• leishmanióza viscerální farmakoterapie   patologie   MeSH
• léková rezistence genetika   MeSH
• membránové transportní proteiny genetika   MeSH
• myši inbrední BALB C parazitologie   MeSH
• myši MeSH
• Phlebotomus parazitologie   MeSH
• protozoální geny MeSH
• Psychodidae parazitologie   MeSH
• zvířata MeSH
• Check Tag
• myši MeSH
• zvířata MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH
• Názvy látek
• antiprotozoální látky MeSH
• fosforylcholin MeSH
• membránové transportní proteiny MeSH
• miltefosine MeSH Prohlížeč