Biosynthesis of human myeloperoxidase

Nauseef, William M.

doi:10.1016/j.abb.2018.02.001

Cited by 47 publications

(56 citation statements)

References 155 publications

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“…The correct incorporation of the heme porphyrin ring is essential for the nascent protein’s exit from the ER and indeed for protein functionality 16 , requiring hydrogen peroxide provided by the dual oxidase (DUOX) family of proteins present in the thyroid follicular cell membrane and are closely associated with TPO 10, 42, 43 . Anticipating that the autocatalytic process of heme incorporation might be reduced during mammalian expression due to a lack of hydrogen peroxide, the media was supplemented with hydrogen peroxide as well as hematin, resulting in enzyme activity for ΔproTPOe-8His but not ΔproTPOe-GCN4 10 .…”

Section: Discussionmentioning

confidence: 99%

“…Some insights may be gleaned from studies on MPO, given its common ancestry and function with TPO. MPO dimerisation occurs in the secretory pathway during proteolytic processing 16 . In TPO biosynthesis, the propeptide is cleaved after exit from the Golgi apparatus and dimerisation is likely to occur prior to reaching the plasma membrane 10 .…”

Section: Discussionmentioning

confidence: 99%

“…As such, dimerisation may occur during the secretory pathway as in MPO, although MPO is not localized in the plasma membrane like TPO, providing additional sites at which TPO may dimerise. A small percentage (∼10%) of MPO is secreted as a fully functional monomer with exactly half the enzyme activity compared to the dimer 16 . As such, MPO activity does not require dimerization and the functional advantages of dimerisation are not understood.…”

Section: Discussionmentioning

confidence: 99%

“…MPO functions as a dimer, and the conserved cysteine at residue 296 in TPO’s MPO-like domain would suggest a likely site of dimerisation. Despite this, no evidence revealing where in the cell TPO dimers are formed is available, however it has been shown that MPO dimerises after leaving the ER 10, 16 . In contrast, it has been shown that MPO can exist and function as a monomer in vivo despite usually presenting as a dimer 16 .…”

Section: Introductionmentioning

confidence: 99%

“…Despite this, no evidence revealing where in the cell TPO dimers are formed is available, however it has been shown that MPO dimerises after leaving the ER 10, 16 . In contrast, it has been shown that MPO can exist and function as a monomer in vivo despite usually presenting as a dimer 16 . In the absence of structural characterisation, we previously modelled TPO as homodimer bound by the conserved cysteine residue Cys296 8 .…”

Section: Introductionmentioning

confidence: 99%

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Structural studies of thyroid peroxidase show the monomer interacting with autoantibodies in thyroid autoimmune disease

Williams

Hoke

et al. 2019

Preprint

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25Thyroid peroxidase (TPO) is a critical membrane-bound enzyme involved in the biosynthesis of 26 multiple thyroid hormones, and is a major autoantigen in autoimmune thyroid diseases such as 27 Graves' disease and Hashimoto's thyroiditis. Here we report the biophysical and structural 28 characterisation of two novel TPO constructs containing only the ectodomain of TPO and lacking the 29 propeptide. Both constructs were enzymatically active and able to bind the patient-derived TR1.9 30 autoantibody. Analytical ultra-centrifugation data suggests that TPO can exist as both a monomer 31 and a dimer. Combined with negative stain electron microscopy and molecular dynamics 32 simulations, these data show that TR1.9 autoantibody preferentially binds the TPO monomer, 33 revealing conformational changes that bring together previously disparate residues into a 34 continuous epitope. In addition to providing plausible structural models of a TPO-autoantibody 35 complex, this study provides validated TPO constructs that will facilitate further characterization, 36 and advances our understanding of the structural, functional and antigenic characteristics of TPO, a 37 molecule behind some of the most common autoimmune diseases. 38 39 40 41 48 (Hashimoto's disease) and hyperthyroidism (Grave's disease) 2,3. AITDs are some of the most 49 common autoimmune diseases in the developed world, with Hashimoto's disease being a strong risk 50 factor for thyroid cancer 4. TPO is suspected to be involved in the pathogenesis of Hashimoto's 51 thyroiditis (prevalence 300-2980 cases per 100,000 in the Western world), leading to thyrocyte 52 destruction via CD8+ T-cell infiltration resulting in hypothyroidism 1,3,5. This incidence rate can be 53 compared to other autoimmune diseases -for example type 1 diabetes, which has an incidence in 54 the developed world of 310-570 cases per 100,000 patients -demonstrating the immense disease 55 burden caused by AITDs 5. The pathogeneses that underlies these autoimmune diseases is complex, 56 however the lack of any tertiary or quaternary structure of TPO complicates matters. The absence of 57 a structure in which to understand binding of anti-TPO antibodies, which are prevalent almost 58 ubiquitously (>95%) in cases of destructive thyroiditis, complicates the understanding of the 59 pathogenesis and nature of the disease. The precise mechanism by which these antibodies cause 60 damage is uncertain 2. Additionally, in some cases AITDs can occur without these autoantibodies 61 being present, and transplacental passage of anti-TPO antibodies does not necessarily cause thyroid 62 damage in the offspring 3,6,7. Despite this, transplacental passage of these autoantibodies can 63 potentially have cognitive effects on the child. In addition, antibodies to thyroglobulin (Tg) and 64 thyroid stimulating hormone receptor have been identified in both conditions, indicating that there 65 may be multiple antigens in AITD pathogenesis 2. 66TPO is a member of the animal heme peroxidase family, which also includes myelope...

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Structural studies of thyroid peroxidase show the monomer interacting with autoantibodies in thyroid autoimmune disease

Williams

Hoke

et al. 2019

Preprint

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Myeloperoxidase Controls Bone Turnover by Suppressing Osteoclast Differentiation Through Modulating Reactive Oxygen Species Level

Zhao

Lin

et al. 2020

Journal of Bone and Mineral Research

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Myeloperoxidase (MPO) is a heme peroxidase that plays an important role in innate immunity for host defense against invading microorganisms by catalyzing hydrogen peroxide (H2O2)‐mediated reactions. Although many reports indicate MPO exerts beneficial or detrimental effects on a variety of inflammatory diseases, little is known with regard to its functional role in bone homeostasis in vivo. Here, our work demonstrates that MPO was transcriptionally downregulated in response to osteoclastogenic stimuli and that exogenous alteration of MPO expression negatively regulated osteoclast (OC) differentiation in vitro. Genetic ablation of Mpo resulted in osteoporotic phenotypes and potentiated bone‐resorptive capacity in mice. Mechanistically, accumulation of intracellular H2O2 and reactive oxygen species (ROS) were observed in MPO deficiency, and MPO overexpression suppressed ROS production in mouse OC precursors. Moreover, a ROS scavenger Tempol inhibited the effect of MPO deficiency on OC formation and function as well as on receptor activator of nuclear factor‐κB ligand (RANKL)‐initiated transduction signal activation including NF‐κB, mitogen‐activated protein kinases (MAPKs), and Akt, indicating the increased ROS caused by MPO deficiency contributes to osteoclastogenesis. Taken together, our data demonstrate that MPO has a protective role in bone turnover by limiting osteoclastogenesis and bone resorption physiologically through modulating intracellular H2O2 level. © 2020 The Authors. Journal of Bone and Mineral Research published by Wiley Periodicals LLC on behalf of American Society for Bone and Mineral Research (ASBMR).

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Myeloid CFTR loss-of-function causes persistent neutrophilic inflammation in cystic fibrosis

Jennings

Wellems

et al. 2020

Journal of Leukocyte Biology

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Persistent neutrophilic inflammation is a hallmark of cystic fibrosis (CF). However, the mechanisms underlying this outstanding pathology remain incompletely understood. Here, we report that CFTR in myeloid immune cells plays a pivotal role in control of neutrophilic inflammation. Myeloid CFTR-Knockout (Mye-Cftr−/−) mice and congenic wild-type (WT) mice were challenged peritoneally with zymosan particles at different doses, creating aseptic peritonitis with varied severity. A high-dose challenge resulted in significantly higher mortality in Mye-Cftr−/− mice, indicating an intrinsic defect in host control of inflammation in mice whose myeloid cells lack CF. The low-dose challenge demonstrated an impaired resolution of inflammation in Mye-Cftr−/− mice, reflected by a significant overproduction of proinflammatory cytokines, including neutrophil chemokines MIP-2 and KC, and sustained accumulation of neutrophils. Tracing neutrophil mobilization in vivo demonstrated that myeloid CF mice recruited significantly more neutrophils than did WT mice. Pulmonary challenge with zymosan elicited exuberant inflammation in the lung and recapitulated the findings from peritoneal challenge. To determine the major type of cell that was primarily responsible for the over-recruitment of neutrophils, we purified and cultured ex vivo zymosan-elicited peritoneal neutrophils and macrophages. The CF neutrophils produced significantly more MIP-2 than did the WT counterparts, and peripheral blood neutrophils isolated from myeloid CF mice also produced significantly more MIP-2 after zymosan stimulation in vitro. These data altogether suggest that CFTR dysfunction in myeloid immune cells, especially neutrophils, leads to hyperinflammation and excessive neutrophil mobilization in the absence of infection. Thus, dysregulated inflammation secondary to abnormal or absent CFTR in myeloid cells may underlie the clinically observed neutrophilic inflammation in CF. K E Y W O R D S cystic fibrosis, neutrophil defect, neutrophilic inflammation 1 INTRODUCTION Cystic fibrosis (CF) is caused by mutations in the CF transmembrane conductance regulator gene (cftr) that encodes CFTR, a cAMPactivated chloride channel. 1 The most severe and life-threatening pathology occurs in the lung where chronic bacterial infection, persis-Abbreviations: ABAH, 4-amino-benzoic acid hydrazide; CMFDA, 5-chloromethylfluorescein diacetate; CF, cystic fibrosis; GRO, growth-related oncogene; HOCl, hypochlorous acid; H 2 O 2 , hydrogen peroxide; MPO, myeloperoxidase; NaN 3 , sodium azide; ROS, reactive oxygen species; WT, wild-type. tent neutrophilic inflammation, and purulent small airway obstruction lead to bronchiectasis and pulmonary failure. 2 The lungs of CF newborns are free from inflammation, 3,4 suggesting that CF lung inflammatory disease is acquired after birth. As infection and inflammation are highly associated, it is difficult to study CF lung inflammation without the interference of infection by using the commonly used lung infection model. Thus, outstanding questions ...

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Biosynthesis of human myeloperoxidase

Cited by 47 publications

References 155 publications

Structural studies of thyroid peroxidase show the monomer interacting with autoantibodies in thyroid autoimmune disease

Structural studies of thyroid peroxidase show the monomer interacting with autoantibodies in thyroid autoimmune disease

Myeloperoxidase Controls Bone Turnover by Suppressing Osteoclast Differentiation Through Modulating Reactive Oxygen Species Level

Myeloid CFTR loss-of-function causes persistent neutrophilic inflammation in cystic fibrosis

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