scholarly journals Ca2+ Regulates ERp57-Calnexin Complex Formation

Molecules ◽  
2021 ◽  
Vol 26 (10) ◽  
pp. 2853
Author(s):  
Yuya Tanikawa ◽  
Shingo Kanemura ◽  
Dai Ito ◽  
Yuxi Lin ◽  
Motonori Matsusaki ◽  
...  
Keyword(s):  
Molecular Mechanisms ◽  
Critical Role ◽  
Covalent Bond ◽  
Human Leukocyte ◽  
Titration Calorimetry ◽  
Oxidative Folding ◽  
Leukocyte Antigen ◽  
Heavy Chains ◽  
Oxidative Protein Folding ◽  
Chaperone Network

ERp57, a member of the protein disulfide isomerase family, is a ubiquitous disulfide catalyst that functions in the oxidative folding of various clients in the mammalian endoplasmic reticulum (ER). In concert with ER lectin-like chaperones calnexin and calreticulin (CNX/CRT), ERp57 functions in virtually all folding stages from co-translation to post-translation, and thus plays a critical role in maintaining protein homeostasis, with direct implication for pathology. Here, we present mechanisms by which Ca2+ regulates the formation of the ERp57-calnexin complex. Biochemical and isothermal titration calorimetry analyses revealed that ERp57 strongly interacts with CNX via a non-covalent bond in the absence of Ca2+. The ERp57-CNX complex not only promoted the oxidative folding of human leukocyte antigen heavy chains, but also inhibited client aggregation. These results suggest that this complex performs both enzymatic and chaperoning functions under abnormal physiological conditions, such as Ca2+ depletion, to effectively guide proper oxidative protein folding. The findings shed light on the molecular mechanisms underpinning crosstalk between the chaperone network and Ca2+.

The Oxidative Folding and Misfolding of Human Leukocyte Antigen-B27

2011 ◽  
Vol 15 (3) ◽  
pp. 669-684 ◽  
Author(s):  
Antony N. Antoniou ◽  
David B. Guiliano ◽  
Izabela Lenart ◽  
Garth Burn ◽  
Simon J. Powis
Keyword(s):  
Human Leukocyte Antigen ◽  
Human Leukocyte ◽  
Oxidative Folding ◽  
Leukocyte Antigen

scholarly journals HLA-B*15:01 is associated with asymptomatic SARS-CoV-2 infection

2021 ◽  
Author(s):  
Danillo G Augusto ◽  
Tasneem Yusufali ◽  
Noah D Peyser ◽  
Xochitl Butcher ◽  
Gregory M Marcus ◽  
...  
Keyword(s):  
Critical Role ◽  
Human Leukocyte ◽  
Asymptomatic Infection ◽  
Baseline Survey ◽  
Symptomatic Infection ◽  
Symptomatic Disease ◽  
Leukocyte Antigen ◽  
Hla Genotyping ◽  
Asymptomatic Individuals ◽  
Test Result

Background. Evidence has shown that a large proportion of SARS-CoV-2 infected individuals do not experience symptomatic disease. Owing to its critical role in immune response, we hypothesized that variation in the human leukocyte antigen (HLA) loci may underly asymptomatic infection. Methods. We enrolled 29,947 individuals registered in the National Marrow Donor Program for whom high-resolution HLA genotyping data were available in a smartphone-based study designed to track COVID-19 symptoms and outcomes. Among 21,893 individuals who completed the baseline survey, our discovery (N=640) and replication (N=788) cohorts were comprised of self-identified White subjects who reported a positive test result for SARS-CoV-2. We tested for association of five HLA loci (HLA-A, -B, -C, -DRB1, -DQB1) with asymptomatic vs. symptomatic infection. Results. HLA-B*15:01 was significantly increased in asymptomatic individuals in the discovery cohort compared to symptomatic (OR = 2.45; 95%CI 1.38-4.24, p = 0.0016, pcorr = 0.048), and we reproduced this association in the replication cohort (OR= 2.32; 95%CI = 1.10-4.43, p = 0.017). We found robust association of HLA-B*15:01 in the combined dataset (OR=2.40 95% CI = 1.54-3.64; p = 5.67 x10-5) and observed that homozygosity of this allele increases more than eight times the chance of remaining asymptomatic after SARS-CoV-2 infection (OR = 8.58, 95%CI = 1.74-34.43, p = 0.003). Finally, we demonstrated the association of HLA-B*15:01 with asymptomatic SARS-Cov-2 infection is enhanced by the presence of HLA-DRB1*04:01 Conclusion. HLA-B*15:01 is strongly associated with asymptomatic infection with SARS-CoV-2 and is likely to be involved in the mechanism underlying early viral clearance.

scholarly journals Spondyloarthritis and the Human Leukocyte Antigen (HLA)-B*27 Connection

2021 ◽  
Vol 12 ◽  
Author(s):  
Chengappa G. Kavadichanda ◽  
Jie Geng ◽  
Sree Nethra Bulusu ◽  
Vir Singh Negi ◽  
Malini Raghavan
Keyword(s):  
Endoplasmic Reticulum ◽  
Human Leukocyte Antigen ◽  
Human Leukocyte ◽  
Hla Class I ◽  
Clinical Aspects ◽  
Susceptibility Loci ◽  
New Bone Formation ◽  
High Association ◽  
Leukocyte Antigen ◽  
Heavy Chains

Heritability of Spondyloarthritis (SpA) is highlighted by several familial studies and a high association with the presence of human leukocyte antigen (HLA)-B*27. Though it has been over four decades since the association of HLA-B*27 with SpA was first determined, the pathophysiological roles played by specific HLA-B*27 allotypes are not fully understood. Popular hypotheses include the presentation of arthritogenic peptides, triggering of endoplasmic reticulum (ER) stress by misfolded HLA-B*27, and the interaction between free heavy chains or heavy chain homodimers of HLA-B*27 and immune receptors to drive IL-17 responses. Several non-HLA susceptibility loci have also been identified for SpA, including endoplasmic reticulum aminopeptidases (ERAP) and those related to the IL-23/IL-17 axes. In this review, we summarize clinical aspects of SpA including known characteristics of gut inflammation, enthesitis and new bone formation and the existing models for understanding the association of HLA-B*27 with disease pathogenesis. We also examine newer insights into the biology of HLA class I (HLA-I) proteins and their implications for expanding our understanding of HLA-B*27 contributions to SpA pathogenesis.

scholarly journals arcasHLA: high resolution HLA typing from RNA seq

2018 ◽  
Author(s):  
Rose Orenbuch ◽  
Ioan Filip ◽  
Devon Comito ◽  
Jeffrey Shaman ◽  
Itsik Pe'er ◽  
...  
Keyword(s):  
Rna Sequencing ◽  
Mhc Class Ii ◽  
Critical Role ◽  
Human Leukocyte ◽  
Hla Typing ◽  
Sequencing Data ◽  
Leukocyte Antigen ◽  
Hla Genes ◽  
Biological Dataset ◽  
High Level

Human leukocyte antigen (HLA) locus makes up the major compatibility complex (MHC) and plays a critical role in host response to disease, including cancers and autoimmune disorders. In the clinical setting, HLA typing is necessary for determining tissue compatibility. Recent improvements in the quality and accessibility of next-generation sequencing have made HLA typing from standard short-read data practical. However, this task remains challenging given the high level of polymorphism and homology between the HLA genes. HLA typing from RNA sequencing is further complicated by post-transcriptional splicing and bias due to amplification. Here, we present arcasHLA: a fast and accurate in silico tool that infers HLA genotypes from RNA sequencing data. Our tool outperforms established tools on the gold-standard benchmark dataset for HLA typing in terms of both accuracy and speed, with an accuracy rate of 100% at two field precision for MHC class I genes, and over 99.7% for MHC class II. Importantly, arcasHLA takes as its input pre-aligned BAM files, and outputs three-field resolution for all HLA genes in less than 2 minutes. Finally, we discuss evaluate the performance of our tool on a new biological dataset of 447 single-end total RNA samples from nasopharyngeal swabs, and establish the applicability of arcasHLA in metatranscriptome studies. arcasHLA is available at https://github.com/RabadanLab/arcasHLA.

scholarly journals BONE MARROW HOMING AND ENGRAFTMENT DEFECTS OF HUMAN HEMATOPOIETIC STEM AND PROGENITOR CELLS

2017 ◽  
Vol 9 (1) ◽  
pp. e2017032 ◽  
Author(s):  
Giovanni Caocci ◽  
Giorgio La Nasa
Keyword(s):  
Stem Cells ◽  
Bone Marrow ◽  
Critical Role ◽  
Human Leukocyte ◽  
Hematopoietic Stem ◽  
Hematological Disorders ◽  
Leukocyte Antigen ◽  
Complex Process ◽  
Stem And Progenitor Cells ◽  
Conditioning Regimens

Homing of hematopoietic stem cells (HSC) to their microenvironment niches in the bone marrow is a complex process with a critical role in repopulation of the bone marrow after transplantation.  This active process allows for migration of HSC from peripheral blood and their successful anchoring in bone marrow before proliferation. The process of engraftment starts with the onset of proliferation and must therefore be functionally dissociated from the former process. In this overview we analyse the characteristics of stem cells (SCs) with particular emphasis on their plasticity and ability to find their way home to the bone marrow. We also address the problem of graft failure which remains an important contributor to morbidity and mortality after allogeneic hematopoietic stem cell transplantation (HSCT). Within this context, we discuss non-malignant and malignant hematological disorders treated with reduced intensity conditioning regimens or grafts from human leukocyte antigen (HLA)-mismatched donors.

The HLA system: immunobiology, HLA typing, antibody screening and crossmatching techniques

2010 ◽  
Vol 63 (5) ◽  
pp. 387-390 ◽  
Author(s):  
W M Howell ◽  
V Carter ◽  
B Clark
Keyword(s):  
Critical Role ◽  
Human Leukocyte ◽  
Hla Typing ◽  
Antibody Screening ◽  
Leukocyte Antigen ◽  
Hla System ◽  
Clinical Transplantation ◽  
Cross Matching ◽  
Immunological Barrier ◽  
Introductory Review

The Human Leukocyte Antigen (HLA) system plays a critical role in regulating the immune response. As a consequence of its role in immune regulation and exquisite polymorphism, the HLA system also constitutes an immunological barrier which must be avoided or otherwise overcome in clinical transplantation. This introductory review provides a brief summary of the immunobiology of the HLA system and methodology for HLA typing, antibody screening and patient-donor cross-matching. This constitutes a basis for consideration of the importance of these procedures in the system-specific reviews which follow.

scholarly journals Interaction of Class I Human Leukocyte Antigen (HLA-I) Molecules with Insulin Receptors and Its Effect on the Insulin-Signaling Cascade

1997 ◽  
Vol 8 (12) ◽  
pp. 2463-2474 ◽  
Author(s):  
Tirunelveli S. Ramalingam ◽  
Abhijit Chakrabarti ◽  
Michael Edidin
Keyword(s):  
Insulin Receptor ◽  
Human Leukocyte ◽  
Insulin Receptors ◽  
Class I ◽  
Activity Increase ◽  
Complex Molecules ◽  
Leukocyte Antigen ◽  
Heavy Chains ◽  
Functional Consequences ◽  
Phosphoinositide 3 Kinase

Insulin receptor (IR) and class I major histocompatibility complex molecules associate with one another in cell membranes, but the functional consequences of this association are not defined. We found that IR and human class I molecules (HLA-I) associate in liposome membranes and that the affinity of IR for insulin and its tyrosine kinase activity increase as the HLA:IR ratio increases over the range 1:1 to 20:1. The same relationship between HLA:IR and IR function was found in a series of B-LCL cell lines. The association of HLA-I and IR depends upon the presence of free HLA heavy chains. All of the effects noted were reduced or abrogated if liposomes or cells were incubated with excess HLA-I light chain, β2-microglobulin. Increasing HLA:IR also enhanced phosphorylation of insulin receptor substrate-1 and the activation of phosphoinositide 3-kinase. HLA-I molecules themselves were phosphorylated on tyrosine and associated with phosphoinositide 3-kinase when B-LCL were stimulated with insulin.

scholarly journals arcasHLA: high-resolution HLA typing from RNAseq

2019 ◽  
Vol 36 (1) ◽  
pp. 33-40 ◽  
Author(s):  
Rose Orenbuch ◽  
Ioan Filip ◽  
Devon Comito ◽  
Jeffrey Shaman ◽  
Itsik Pe’er ◽  
...  
Keyword(s):  
Rna Sequencing ◽  
Critical Role ◽  
Human Leukocyte ◽  
Hla Typing ◽  
Supplementary Information ◽  
Sequencing Data ◽  
Leukocyte Antigen ◽  
Biological Dataset ◽  
Hla Genotypes ◽  
High Level

Abstract Motivation The human leukocyte antigen (HLA) locus plays a critical role in tissue compatibility and regulates the host response to many diseases, including cancers and autoimmune di3orders. Recent improvements in the quality and accessibility of next-generation sequencing have made HLA typing from standard short-read data practical. However, this task remains challenging given the high level of polymorphism and homology between HLA genes. HLA typing from RNA sequencing is further complicated by post-transcriptional modifications and bias due to amplification. Results Here, we present arcasHLA: a fast and accurate in silico tool that infers HLA genotypes from RNA-sequencing data. Our tool outperforms established tools on the gold-standard benchmark dataset for HLA typing in terms of both accuracy and speed, with an accuracy rate of 100% at two-field resolution for Class I genes, and over 99.7% for Class II. Furthermore, we evaluate the performance of our tool on a new biological dataset of 447 single-end total RNA samples from nasopharyngeal swabs, and establish the applicability of arcasHLA in metatranscriptome studies. Availability and implementation arcasHLA is available at https://github.com/RabadanLab/arcasHLA. Supplementary information Supplementary data are available at Bioinformatics online.

scholarly journals The Molecular Complex between Staphylococcal Adhesin SpsD and Fibronectin Sustains Mechanical Forces in the Nanonewton Range

mBio ◽  
2020 ◽  
Vol 11 (4) ◽  
Author(s):  
Felipe Viela ◽  
Marion Mathelié-Guinlet ◽  
Giampiero Pietrocola ◽  
Pietro Speziale ◽  
Yves F. Dufrêne
Keyword(s):  
Epithelial Cells ◽  
Molecular Mechanisms ◽  
Critical Role ◽  
Covalent Bond ◽  
Dynamic Force ◽  
Staphylococcus Pseudintermedius ◽  
Content Type ◽  
Intrinsically Disordered ◽  
Tract Infections ◽  
Β Sheet

ABSTRACT The bacterial pathogen Staphylococcus pseudintermedius is involved in canine otitis externa and pyoderma as well as in surgical wound and urinary tract infections. Invasion of canine epithelial cells is promoted by S. pseudintermedius fibronectin (Fn)-binding proteins SpsD and SpsL through molecular interactions that are currently unknown. By means of single-molecule experiments, we discover that both adhesins have distinct molecular mechanisms for binding to Fn. We show that the SpsD-Fn interaction has a strength equivalent to that of a covalent bond (∼1.5 to 1.8 nN), which is an order of magnitude stronger than the binding force of classical receptor-ligand complexes. We suggest that this extreme mechanostability originates from the β-sheet organization of a tandem β-zipper. Upon binding to FnI modules, the intrinsically disordered binding sequences of SpsD would shift into an ordered structure by forming additional β-strands along triple peptide β-sheets in the Fn molecule. Dynamic force measurements reveal an unexpected behavior, i.e., that strong bonds are activated by mechanical tension as observed with catch bonds. By contrast, the SpsL-Fn interaction involves multiple weak bonds (∼0.2 nN) that rupture sequentially under force. Together with the recently described dock, lock, and latch complex, the ultrastrong interaction unraveled here is among the strongest noncovalent biological interaction measured to date. Our findings may find applications for the identification of inhibitory compounds to treat infections triggered by pathogens engaged in tandem β-zipper interactions. IMPORTANCE Binding of Staphylococcus pseudintermedius surface proteins SpsD and SpsL to fibronectin (Fn) plays a critical role in the invasion of canine epithelial cells. Here, we discover that both adhesins have different mechanisms for binding to Fn. The force required to separate SpsD from Fn is extremely strong, consistent with the unusual β-sheet organization of a high-affinity tandem β-zipper. By contrast, unbinding of the SpsL-Fn complex involves the sequential rupture of single weak bonds. Our findings may be of biological relevance as SpsD and SpsL are likely to play complementary roles during invasion. While the SpsD β-zipper supports strong bacterial adhesion and triggers invasion, the weak SpsL interaction would favor fast detachment, enabling the pathogen to colonize new sites.

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