Sec62 promotes gastric cancer metastasis through mediating UPR-induced autophagy activation.

BACKGROUND AND AIMS: Sec62 is a membrane protein of the endoplasmic reticulum that facilitates protein transport. Its role in cancer is increasingly recognised, but remains largely unknown. We investigated the functional role of Sec62 in gastric cancer (GC) and its underlying mechanism. METHODS: Bioinformatics, tissue microarray, immunohistochemistry (IHC), western blotting (WB), quantitative polymerase chain reaction (qPCR), and immunofluorescence were used to examine the expression of target genes. Transwell, scratch healing assays, and xenograft models were used to evaluate cell migration and invasion. Transmission electron microscopy and mRFP-GFP-LC3 double-labeled adenoviruses were used to monitor autophagy. Co-immunoprecipitation (CO-IP) was performed to evaluate the binding activity between the proteins. RESULTS: Sec62 expression was upregulated in GC, and Sec62 upregulation was an independent predictor of poor prognosis. Sec62 overexpression promoted GC cell migration and invasion both in vitro and in vivo. Sec62 promoted migration and invasion by affecting TIMP-1 and MMP2/9 balance. Moreover, Sec62 could activate autophagy by upregulating PERK/ATF4 expression and binding to LC3II with concomitant FIP200/Beclin-1/Atg5 activation. Furthermore, autophagy blockage impaired the promotive effects of Sec62 on GC cell migration and invasion, whereas autophagy activation rescued the inhibitory effect of Sec62 knockdown on GC metastasis. Notably, Sec62 inhibition combined with autophagy blockage exerted a synergetic anti-metastatic effect in vitro and in vivo. CONCLUSION: Sec62 promotes GC metastasis by activating autophagy and subsequently regulating TIMP-1 and MMP2/9 balance. The activation of autophagy by Sec62 may involve the unfolded protein response (UPR)-related PERK/ATF4 pathway and binding of LC3II during UPR recovery involving FIP200/Beclin-1/Atg5 upregulation. Specifically, the dual inhibition of Sec62 and autophagy may provide a promising therapeutic strategy for GC metastasis.

Quantitative prediction of pharmacokinetic properties of drugs in humans: Recent advance in in vitro models to predict the impact of efflux transporters in the small intestine and blood-brain barrier.

Efflux transport systems are essential to suppress the absorption of xenobiotics from the intestinal lumen and protect the critical tissues at the blood-tissue barriers, such as the blood-brain barrier. The function of drug efflux transport is dominated by various transporters. Accumulated clinical evidences have revealed that genetic variations of the transporters, together with coadministered drugs, affect the expression and/or function of transporters and subsequently the pharmacokinetics of substrate drugs. Thus, in the preclinical stage of drug development, quantitative prediction of the impact of efflux transporters as well as that of uptake transporters and metabolic enzymes on the pharmacokinetics of drugs in humans has been performed using various in vitro experimental tools. Various kinds of human-derived cell systems can be applied to the precise prediction of drug transport in humans. Mathematical modeling consisting of each intrinsic metabolic or transport process enables us to understand the disposition of drugs both at the organ level and at the level of the whole body by integrating a variety of experimental results into model parameters. This review focuses on the role of efflux transporters in the intestinal absorption and brain distribution of drugs, in addition to recent advances in predictive tools and methodologies.

Deep impact of the inactivation of the SecA2-only protein export pathway on the proteosurfaceome of Listeria monocytogenes.

Listeria monocytogenes presents a dimorphism associated to the SecA2 activity with cells having a normal rod shape or a dysmorphic elongated filamentous form. Besides variation of the cell and colony morphotype, this cell differentiation has profound ecophysiological and physiopathological implications with collateral effects on virulence and pathogenicity, biotope colonisation, bacterial adhesion and biofilm formation. This suggests the SecA2-only protein export could influence the listerial cell surface, which was investigated first by characterising its properties in L. monocytogenes wt and ΔsecA2. The degree of hydrophilicity and Lewis acid-base properties appeared significantly affected upon SecA2 inactivation. As modification of electrostatic properties would owe to modification in the composition of cell-surface proteins, the proteosurfaceome was further investigated by shotgun label-free proteomic analysis with a comparative relative quantitative approach. Following secretomic analysis, the protein secretion routes of the identified proteins were mapped considering the cognate transport and post-translocational maturation systems, as well as protein categories and subcellular localisation. Differential protein abundance profiles coupled to network analysis revealed the SecA2 dependence of 48 proteins, including some related to cell envelope biogenesis, translation and protein export, which could account for modifications of adhesion and surface properties of L. monocytogenes upon SecA2 inactivation. This investigation unravelled the profound influence of SecA2 activity on the cell surface properties and proteosurfaceome of L. monocytogenes, which provides advanced insights about its ecophysiopathology. SIGNIFICANCE: L. monocytogenes is a foodborne zoonotic pathogen and etiological agent of human listeriosis. This species presents a cellular dimorphism associated to the SecA2 activity that has profound physiopathological and ecophysiological implications with collateral effects on bacterial virulence and colonisation. To explore the influence of the SecA2-only protein export on the listerial cell, the surface properties of L. monocytogenes expressing or depleted of SecA2 was characterised by microelectrophoresis, microbial affinity to solvents and contact angles analyses. As modifications of hydrophilicity and Lewis acid-base electrostatic properties would owe to modification in the composition of cell-surface proteins, the proteinaceous subset of the surfaceome, i.e. the proteosurfaceome, was investigated further by shotgun label-free proteomic analysis. This subproteome appeared quite impacted upon SecA2 inactivation with the identification of proteins accounting for modifications in the cell surface properties. The profound influence of SecA2 activity on the cell surface of L. monocytogenes was unravelled, which provides advanced insights about its ecophysiopathology.

Aging power spectrum of membrane protein transport and other subordinated random walks.

Single-particle tracking offers detailed information about the motion of molecules in complex environments such as those encountered in live cells, but the interpretation of experimental data is challenging. One of the most powerful tools in the characterization of random processes is the power spectral density. However, because anomalous diffusion processes in complex systems are usually not stationary, the traditional Wiener-Khinchin theorem for the analysis of power spectral densities is invalid. Here, we employ a recently developed tool named aging Wiener-Khinchin theorem to derive the power spectral density of fractional Brownian motion coexisting with a scale-free continuous time random walk, the two most typical anomalous diffusion processes. Using this analysis, we characterize the motion of voltage-gated sodium channels on the surface of hippocampal neurons. Our results show aging where the power spectral density can either increase or decrease with observation time depending on the specific parameters of both underlying processes.

The Influence of OAT1 Density and Functionality on Indoxyl Sulfate Transport in the Human Proximal Tubule: An Integrated Computational and In Vitro Study.

Research has shown that traditional dialysis is an insufficient long-term therapy for patients suffering from end-stage kidney disease due to the high retention of uremic toxins in the blood as a result of the absence of the active transport functionality of the proximal tubule (PT). The PT's function is defined by the epithelial membrane transporters, which have an integral role in toxin clearance. However, the intricate PT transporter-toxin interactions are not fully explored, and it is challenging to decouple their effects in toxin removal in vitro. Computational models are necessary to unravel and quantify the toxin-transporter interactions and develop an alternative therapy to dialysis. This includes the bioartificial kidney, where the hollow dialysis fibers are covered with kidney epithelial cells. In this integrated experimental-computational study, we developed a PT computational model that focuses on indoxyl sulfate (IS) transport by organic anionic transporter 1 (OAT1), capturing the transporter density in detail along the basolateral cell membrane as well as the activity of the transporter and the inward boundary flux. The unknown parameter values of the OAT1 density (1.15×107 transporters µm-2), IS uptake (1.75×10-5 µM-1 s-1), and dissociation (4.18×10-4 s-1) were fitted and validated with experimental LC-MS/MS time-series data of the IS concentration. The computational model was expanded to incorporate albumin conformational changes present in uremic patients. The results suggest that IS removal in the physiological model was influenced mainly by transporter density and IS dissociation rate from OAT1 and not by the initial albumin concentration. While in uremic conditions considering albumin conformational changes, the rate-limiting factors were the transporter density and IS uptake rate, which were followed closely by the albumin-binding rate and IS dissociation rate. In summary, the results of this study provide an exciting avenue to help understand the toxin-transporter complexities in the PT and make better-informed decisions on bioartificial kidney designs and the underlining transporter-related issues in uremic patients.

Rice SUT and SWEET Transporters.

Sugar transporters play important or even indispensable roles in sugar translocation among adjacent cells in the plant. They are mainly composed of sucrose-proton symporter SUT family members and SWEET family members. In rice, 5 and 21 members are identified in these transporter families, and some of their physiological functions have been characterized on the basis of gene knockout or knockdown strategies. Existing evidence shows that most SUT members play indispensable roles, while many SWEET members are seemingly not so critical in plant growth and development regarding whether their mutants display an aberrant phenotype or not. Generally, the expressions of SUT and SWEET genes focus on the leaf, stem, and grain that represent the source, transport, and sink organs where carbohydrate production, allocation, and storage take place. Rice SUT and SWEET also play roles in both biotic and abiotic stress responses in addition to plant growth and development. At present, these sugar transporter gene regulation mechanisms are largely unclear. In this review, we compare the expressional profiles of these sugar transporter genes on the basis of chip data and elaborate their research advances. Some suggestions concerning future investigation are also proposed.

Ins and Outs: Recent Advancements in Membrane Protein-Mediated Prokaryotic Ferrous Iron Transport.

Iron is an essential nutrient for virtually every living organism, especially pathogenic prokaryotes. Despite its importance, however, both the acquisition and the export of this element require dedicated pathways that are dependent on oxidation state. Due to its solubility and kinetic lability, reduced ferrous iron (Fe2+) is useful to bacteria for import, chaperoning, and efflux. Once imported, ferrous iron may be loaded into apo and nascent enzymes and even sequestered into storage proteins under certain conditions. However, excess labile ferrous iron can impart toxicity as it may spuriously catalyze Fenton chemistry, thereby generating reactive oxygen species and leading to cellular damage. In response, it is becoming increasingly evident that bacteria have evolved Fe2+ efflux pumps to deal with conditions of ferrous iron excess and to prevent intracellular oxidative stress. In this work, we highlight recent structural and mechanistic advancements in our understanding of prokaryotic ferrous iron import and export systems, with a focus on the connection of these essential transport systems to pathogenesis. Given the connection of these pathways to the virulence of many increasingly antibiotic resistant bacterial strains, a greater understanding of the mechanistic details of ferrous iron cycling in pathogens could illuminate new pathways for future therapeutic developments.

Phytosterol accumulation results in ventricular arrhythmia, impaired cardiac function and death in mice.

Heart failure (HF) and cardiac arrhythmias share overlapping pathological mechanisms that act cooperatively to accelerate disease pathogenesis. Cardiac fibrosis is associated with both pathological conditions. Our previous work identified a link between phytosterol accumulation and cardiac injury in a mouse model of phytosterolemia, a rare disorder characterized by elevated circulating phytosterols and increased cardiovascular disease risk. Here, we uncover a previously unknown pathological link between phytosterols and cardiac arrhythmias in the same animal model. Phytosterolemia resulted in inflammatory pathway induction, premature ventricular contractions (PVC) and ventricular tachycardia (VT). Blockade of phytosterol absorption either by therapeutic inhibition or by genetic inactivation of NPC1L1 prevented the induction of inflammation and arrhythmogenesis. Inhibition of phytosterol absorption reduced inflammation and cardiac fibrosis, improved cardiac function, reduced the incidence of arrhythmias and increased survival in a mouse model of phytosterolemia. Collectively, this work identified a pathological mechanism whereby elevated phytosterols result in inflammation and cardiac fibrosis leading to impaired cardiac function, arrhythmias and sudden death. These comorbidities provide insight into the underlying pathophysiological mechanism for phytosterolemia-associated risk of sudden cardiac death.

[Research progress of the role of iodide transporters and its regulatory signal pathways in carcinomas].

Iodine transporters of basement membrane of thyroid follicular epithelial cells can participate and exchange the iodine ions across intracellular and extracellular. Among all of the iodine rich organs, iodine ions which only exist in colloidal of thyroid follicular epithelial cells can be functioned as the raw materials, which after oxidation, iodization and coupling, to synthesize thyroid hormone (TH) and to exert its biological functions. Therefore, the iodine transported function of iodide transporters plays a pivotal role for TH biosynthesis. Furthermore, functional studies show that the abnormal expression or dysfunction of iodide transporters might serves as tumor promoters or inhibitors via regulated the mTOR signal pathway, the MAPKs signal pathway, and the NF-κB signal pathway, together contributed to the regulation of cell proliferation, invasion, metastasis and apoptosis, in which plays the role of non iodide transported function. Therefore, the non iodine transported function of iodide transporters may plays the crucial role of tumor occurrence and progression of carcinoma. Based on this information, present study was devoted to systematic summarize the iodine transported function and non iodine transported function (may affects occurrence and progression of carcinoma) of the classical iodide transporters [sodium iodide symporter (NIS) and pendrin] and novel iodine transporters[ (cystic fibrosis transmembrane conductance regulator (CFTR) , sodium multivitamin transporter (SMVT) , and anoctamin 1 (ANO1) ], respectively, in order to provide a theoretical basis and literature review reference for underlying the mechanism of iodine transporters and its regulated signal pathways for the occurrence and progression of carcinomas.

Secretion of Pertussis Toxin from Bordetella pertussis.

Production and secretion of pertussis toxin (PT) is essential for the virulence of Bordetella pertussis. Due to the large oligomeric structure of PT, transport of the toxin across bacterial membrane barriers represents a significant hurdle that the bacteria must overcome in order to maintain pathogenicity. During the secretion process, PT undergoes a two-step transport process. The first step involves transport of the individual polypeptide chains of PT across the inner membrane utilizing a generalized secretion pathway, most likely the bacterial Sec system. The second step involves the use of a specialized apparatus to transport the toxin across the outer membrane of the bacterial cell. This apparatus, which has been termed the Ptl transporter and which is unique to the PT secretion pathway, is a member of the type IV family of bacterial transporters. Here, the current understanding of the PT secretion process is reviewed including a description of the Ptl proteins that assemble to form the transporter, the general structure of type IV transporters, the known similarities and differences between canonical type IV substrate transport and Ptl-mediated transport of PT, as well as the known sequence of events in the assembly and secretion of PT.

Mechanisms and consequences of casein kinase II and ankyrin-3 regulation of the epithelial Na+ channel.

Activity of the Epithelial Na+ Channel (ENaC) in the distal nephron fine-tunes renal sodium excretion. Appropriate sodium excretion is a key factor in the regulation of blood pressure. Consequently, abnormalities in ENaC function can cause hypertension. Casein Kinase II (CKII) phosphorylates ENaC. The CKII phosphorylation site in ENaC resides within a canonical "anchor" ankyrin binding motif. CKII-dependent phosphorylation of ENaC is necessary and sufficient to increase channel activity and is thought to influence channel trafficking in a manner that increases activity. We test here the hypothesis that phosphorylation of ENaC by CKII within an anchor motif is necessary for ankyrin-3 (Ank-3) regulation of the channel, which is required for normal channel locale and function, and the proper regulation of renal sodium excretion. This was addressed using a fluorescence imaging strategy combining total internal reflection fluorescence (TIRF) microscopy with fluorescence recovery after photobleaching (FRAP) to quantify ENaC expression in the plasma membrane in living cells; and electrophysiology to quantify ENaC activity in split-open collecting ducts from principal cell-specific Ank-3 knockout mice. Sodium excretion studies also were performed in parallel in this knockout mouse. In addition, we substituted a key serine residue in the consensus CKII site in ß-ENaC with alanine to abrogate phosphorylation and disrupt the anchor motif. Findings show that disrupting CKII signaling decreases ENaC activity by decreasing expression in the plasma membrane. In the principal cell-specific Ank-3 KO mouse, ENaC activity and sodium excretion were significantly decreased and increased, respectively. These results are consistent with CKII phosphorylation of ENaC functioning as a "switch" that favors Ank-3 binding to increase channel activity.

Electrophysiological characterization of a diverse group of sugar transporters from Trichoderma reesei.

Trichoderma reesei is an ascomycete fungus known for its capability to secrete high amounts of extracellular cellulose- and hemicellulose-degrading enzymes. These enzymes are utilized in the production of second-generation biofuels and T. reesei is a well-established host for their production. Although this species has gained considerable interest in the scientific literature, the sugar transportome of T. reesei remains poorly characterized. Better understanding of the proteins involved in the transport of different sugars could be utilized for engineering better enzyme production strains. In this study we aimed to shed light on this matter by characterizing multiple T. reesei transporters capable of transporting various types of sugars. We used phylogenetics to select transporters for expression in Xenopus laevis oocytes to screen for transport activities. Of the 18 tested transporters, 8 were found to be functional in oocytes. 10 transporters in total were investigated in oocytes and in yeast, and for 3 of them no transport function had been described in literature. This comprehensive analysis provides a large body of new knowledge about T. reesei sugar transporters, and further establishes X. laevis oocytes as a valuable tool for studying fungal sugar transporters.

PIEZO ion channel is required for root mechanotransduction in Arabidopsis thaliana.

Plant roots adapt to the mechanical constraints of the soil to grow and absorb water and nutrients. As in animal species, mechanosensitive ion channels in plants are proposed to transduce external mechanical forces into biological signals. However, the identity of these plant root ion channels remains unknown. Here, we show that Arabidopsis thaliana PIEZO1 (PZO1) has preserved the function of its animal relatives and acts as an ion channel. We present evidence that plant PIEZO1 is expressed in the columella and lateral root cap cells of the root tip, which are known to experience robust mechanical strain during root growth. Deleting PZO1 from the whole plant significantly reduced the ability of its roots to penetrate denser barriers compared to wild-type plants. pzo1 mutant root tips exhibited diminished calcium transients in response to mechanical stimulation, supporting a role of PZO1 in root mechanotransduction. Finally, a chimeric PZO1 channel that includes the C-terminal half of PZO1 containing the putative pore region was functional and mechanosensitive when expressed in naive mammalian cells. Collectively, our data suggest that Arabidopsis PIEZO1 plays an important role in root mechanotransduction and establish PIEZOs as physiologically relevant mechanosensitive ion channels across animal and plant kingdoms.

Astrocyte-Endotheliocyte Axis in the Regulation of the Blood-Brain Barrier.

The evolution of blood-brain barrier paralleled centralisation of the nervous system: emergence of neuronal masses required control over composition of the interstitial fluids. The barriers were initially created by glial cells, which employed septate junctions to restrict paracellular diffusion in the invertebrates and tight junctions in some early vertebrates. The endothelial barrier, secured by tight and adherent junctions emerged in vertebrates and is common in mammals. Astrocytes form the parenchymal part of the blood-brain barrier and commutate with endothelial cells through secretion of growth factors, morphogens and extracellular vesicles. These secreted factors control the integrity of the blood-brain barrier through regulation of expression of tight junction proteins. The astrocyte-endotheliocyte communications are particularly important in various neurological diseases associated with impairments to the blood-brain barrier. Molecular mechanisms supporting astrocyte-endotheliocyte axis in health and disease are in need of detailed characterisation.

Significant contribution of the CmeABC Efflux pump in high-level resistance to ciprofloxacin and tetracycline in Campylobacter jejuni and Campylobacter coli clinical isolates.

BACKGROUND: Campylobacter resistance to antimicrobial agents is regarded as a major concern worldwide. The aim of this study was to investigate the expression of the CmeABC efflux pump and the RAPD-PCR pattern in drug-resistant Campylobacter isolates. METHODS: A total of 283 stool specimens were collected from children under the age of five with diarrhea. The minimum inhibitory concentration (MIC) of tetracycline and ciprofloxacin was determined by broth microdilution method and E-test, respectively. Detection of tetracycline and ciprofloxacin determinants was done by amplification of tetO gene and PCR-sequencing of the gyrA gene. The cmeABC transcriptional expression was analyzed by Real-time (RT)-PCR. Clonal correlation of resistant strains was determined by RAPD-PCR genotyping. RESULTS: Out of 283 fecal samples, 20 (7.02%) samples were positive for Campylobacter spp. Analysis of duplex PCR assay of the cadF gene showed that 737 and 461 bp amplicons were corresponding to Campylobacter jejuni and Campylobacter coli, respectively. All of the 17 phenotypically tetracycline-resistant Campylobacter isolates harbored the tetO gene. Also, four phenotypically ciprofloxacin-resistant Campylobacter isolates had a point mutation at codon 257 of the gyrA gene (ACA to ATA; Thr > Ile). High-level expression of the cmeA gene was observed in ciprofloxacin-resistant and high-level tetracycline-resistant Campylobacter isolates, suggesting a positive correlation between the cmeA gene expression level and tetracycline resistance level. Moreover, a statistically significant difference was observed in the cmeA gene expression between ciprofloxacin-resistant and ciprofloxacin-susceptible strains, which signifies the crucial contribution of the efflux pump in conferring multiple drug resistance phenotype among Campylobacter spp. RAPD analysis of Campylobacter isolates exhibited 16 different patterns. Simpsone`s diversity index of RAPD-PCR was calculated as 0.85, showing a high level of homogeneity among the population; however, no clear correlation was detected among tetracycline and/or ciprofloxacin resistant isolates. CONCLUSION: Significant contribution of the CmeABC efflux pump in conferring high-level resistance to tetracycline and ciprofloxacin was observed in C. jejuni and C. coli clinical isolates. The resistant phenotype is suggested to be mediated by CmeABC efflux pumps, the tetO gene, and point mutation of the gyrA gene. Genotyping revealed no clonal correlation among resistant strains, indicating distinct evolution of tetracycline and ciprofloxacin resistant genotypes among the isolates.

Two StAR-related lipid transfer proteins play specific roles in endocytosis, exocytosis, and motility in the parasitic protist Entamoeba histolytica.

Lipid transfer proteins (LTPs) are the key contributor of organelle-specific lipid distribution and cellular lipid homeostasis. Here, we report a novel implication of LTPs in phagocytosis, trogocytosis, pinocytosis, biosynthetic secretion, recycling of pinosomes, and motility of the parasitic protist E. histolytica, the etiological agent of human amoebiasis. We show that two StAR-related lipid transfer (START) domain-containing LTPs (named as EhLTP1 and 3) are involved in these biological pathways in an LTP-specific manner. Our findings provide novel implications of LTPs, which are relevant to the elucidation of pathophysiology of the diseases caused by parasitic protists.

The osmotic response capacity of the Antarctic fish Harpagifer antarcticus is insufficient to cope with projected temperature and salinity under climate change.

Over the last decades, climate change has intensified. Temperatures have increased and seawater has become "fresher" in Antarctica, affecting fish such as Harpagifer antarcticus. Thus, this study aimed to evaluate changes in the osmoregulatory response of the Antarctic notothenioid fish Harpagifer antarcticus and evaluate how it will cope with the future climate change and environmental conditions in the Antarctic, and in the hypothetical case that its geographical distribution will be extended to the Magellanes region. The present study was undertaken to determine the interaction between temperature and salinity tolerance (2 °C and 33 psu as the control group, the experimental groups were 5, 8, and 11 °C and 28 and 23 psu) and their effect on the osmoregulatory status of H. antarcticus. We evaluated changes in gill-kidney-intestine NKA activity, gene expression of NKAα, NKCC, CFTR, Aquaporins 1 and 8 in the same tissues, muscle water percentage, and plasma osmolality to evaluate osmoregulatory responses. Plasma osmolality decreased with high temperature, also the gill-kidney-intestine NKA activity, gene expression of NKA α, NKCC, CFTR, Aquaporins 1, and 8 were modified by temperature and salinity. We demonstrated that H. antarcticus can not live in the Magallanes region, due to its incapacity to put up with temperatures over 5 °C and with over 8 °C being catastrophic.

The TIM22 complex mediates the import of sideroflexins and is required for efficient mitochondrial one-carbon metabolism.

Acylglycerol kinase (AGK) is a mitochondrial lipid kinase that contributes to protein biogenesis as a subunit of the TIM22 complex at the inner mitochondrial membrane. Mutations in AGK cause Sengers syndrome, an autosomal recessive condition characterized by congenital cataracts, hypertrophic cardiomyopathy, skeletal myopathy, and lactic acidosis. We mapped the proteomic changes in Sengers patient fibroblasts and AGKKO cell lines to understand the effects of AGK dysfunction on mitochondria. This uncovered down-regulation of a number of proteins at the inner mitochondrial membrane, including many SLC25 carrier family proteins, which are predicted substrates of the complex. We also observed down-regulation of SFXN proteins, which contain five transmembrane domains, and show that they represent a novel class of TIM22 complex substrate. Perturbed biogenesis of SFXN proteins in cells lacking AGK reduces the proliferative capabilities of these cells in the absence of exogenous serine, suggesting that dysregulation of one-carbon metabolism is a molecular feature in the biology of Sengers syndrome.

TonB-dependent transporters in the Bacteroidetes: Unique domain structures and potential functions.

The human gut microbiota endows the host with a wealth of metabolic functions central to health, one of which is the degradation and fermentation of complex carbohydrates. The Bacteroidetes are one of the dominant bacterial phyla of this community and possess an expanded capacity for glycan utilization. This is mediated via the coordinated expression of discrete polysaccharide utilization loci (PUL) that invariantly encode a TonB-dependent transporter (SusC) that works with a glycan-capturing lipoprotein (SusD). More broadly within Gram-negative bacteria, TonB-dependent transporters (TBDTs) are deployed for the uptake of not only sugars, but also more often for essential nutrients such as iron and vitamins. Here, we provide a comprehensive look at the repertoire of TBDTs found in the model gut symbiont Bacteroides thetaiotaomicron and the range of predicted functional domains associated with these transporters and SusD proteins for the uptake of both glycans and other nutrients. This atlas of the B. thetaiotaomicron TBDTs reveals that there are at least three distinct subtypes of these transporters encoded within its genome that are presumably regulated in different ways to tune nutrient uptake.