Metallothionein-3 is a clinical biomarker for tissue zinc levels in nasal mucosa

Suzuki, Masanobu; Ramezanpour, Mahnaz; Cooksley, Clare; Ogi, Kazuhiro; Psaltis, Alkis James; Nakamaru, Yuji; Homma, Akihiro; Wormald, Peter‐John; Vreugde, Sarah

doi:10.1016/j.anl.2021.01.019

Cited by 4 publications

(2 citation statements)

References 33 publications

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“…The metal complement of MT-3 is not known for tissues outside of the neurosystem [ 77 , 78 ]. There are reports that MT-3 can function in zinc acquisition and loading in the immune cells and mucosal epithelial [ 79 , 80 ]. The metal content of renal MT-3 is currently unknown.…”

Section: Discussionmentioning

confidence: 99%

Protein interactions with metallothionein-3 promote vectorial active transport in human proximal tubular cells

et al. 2022

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Metallothionein 3 (MT-3) is a small, cysteine-rich protein that binds to essential metals required for homeostasis, as well as to heavy metals that have the potential to exert toxic effects on cells. MT-3 is expressed by epithelial cells of the human kidney, including the cells of the proximal tubule. Our laboratory has previously shown that mortal cultures of human proximal tubular (HPT) cells express MT-3 and form domes in the cell monolayer, a morphological feature indicative of vectorial active transport, an essential function of the proximal tubule. However, an immortalized proximal tubular cell line HK-2 lacks the expression of MT-3 and fails to form domes in the monolayer. Transfection of HK-2 cells with the MT-3 gene restores dome formation in these cells suggesting that MT-3 is required for vectorial active transport. In order to determine how MT-3 imparts this essential feature to the proximal tubule, we sought to identify proteins that interact either directly or indirectly with MT-3. Using a combination of pulldowns, co-immunoprecipitations, and mass spectrometry analysis, putative protein interactants were identified and subsequently confirmed by Western analysis and confocal microscopy, following which proteins with direct physical interactions were investigated through molecular docking. Our data shows that MT-3 interacts with myosin-9, aldolase A, enolase 1, β-actin, and tropomyosin 3 and that these interactions are maximized at the periphery of the apical membrane of doming proximal tubule cells. Together these observations reveal that MT-3 interacts with proteins involved in cytoskeletal organization and energy metabolism, and these interactions at the apical membrane support vectorial active transport and cell differentiation in proximal tubule cultures.

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Section: Discussionmentioning

confidence: 99%

Protein interactions with metallothionein-3 promote vectorial active transport in human proximal tubular cells

et al. 2022

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“…95 Both hypotheses intersect with Zn deficiency due to its pro-inflammatory and barrier-impairing action, mucins' Zn-binding properties, and their upregulation at low Zn levels. 96 In addition, mucins are strictly connected with the "microbiota" hypothesis, being implicated in bacterial cross-feeding and as AMPs binding factors.…”

Section: Biofilm Impact On Sinuses Mucosamentioning

confidence: 99%

Remodeling of Paranasal Sinuses Mucosa Functions in Response to Biofilm-Induced Inflammation

Kaliniak,

Fiedoruk,

Spałek

et al. 2024

JIR

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Rhinosinusitis (RS) is an acute (ARS) or chronic (CRS) inflammatory disease of the nasal and paranasal sinus mucosa. CRS is a heterogeneous condition characterized by distinct inflammatory patterns (endotypes) and phenotypes associated with the presence (CRSwNP) or absence (CRSsNP) of nasal polyps. Mucosal barrier and mucociliary clearance dysfunction, inflammatory cell infiltration, mucus hypersecretion, and tissue remodeling are the hallmarks of CRS. However, the underlying factors, their priority, and the mechanisms of inflammatory responses remain unclear. Several hypotheses have been proposed that link CRS etiology and pathogenesis with host (eg, "immune barrier") and exogenous factors (eg, bacterial/fungal pathogens, dysbiotic microbiota/biofilms, or staphylococcal superantigens). The abnormal interplay between these factors is likely central to the pathophysiology of CRS by triggering compensatory immune responses. Here, we discuss the role of the sinonasal microbiota in CRS and its biofilms in the context of mucosal zinc (Zn) deficiency, serving as a possible unifying link between five host and "bacterial" hypotheses of CRS that lead to sinus mucosa remodeling. To date, no clear correlation between sinonasal microbiota and CRS has been established. However, the predominance of Corynebacteria and Staphylococci and their interspecies relationships likely play a vital role in the formation of the CRS-associated microbiota. Zn-mediated "nutritional immunity", exerted via calprotectin, alongside the dysregulation of Zn-dependent cellular processes, could be a crucial microbiota-shaping factor in CRS. Similar to cystic fibrosis (CF), the role of SPLUNC1-mediated regulation of mucus volume and pH in CRS has been considered. We complement the biofilms' "mechanistic" and "mucin" hypotheses behind CRS pathogenesis with the "structural" one -associated with bacterial "corncob" structures. Finally, microbiota restoration approaches for CRS prevention and treatment are reviewed, including pre-and probiotics, as well as Nasal Microbiota Transplantation (NMT).

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Comparison of serum zinc levels between patients with sinonasal neutrophilic and eosinophilic inflammatory polyposis and healthy individuals

Ghazizadeh,

Roshanaie,

Barati

2024

Immunity Inflam & Disease

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ObjectivesSome changes in nasal mucus and paranasal sinuses may occur due to zinc deficiency, which can cause chronic rhinosinusitis with nasal polyps (CRSwNP). The current study was designed to compare the serum zinc concentration between patients with chronic rhinosinusitis complicated with eosinophilic or neutrophilic nasal polyps and a control group.MethodsA total of 105 patients participated in the study. Patients in three different groups were evaluated for CRSwNP (35 in the eosinophilia group and 35 in the neutrophil group), and 35 patients underwent surgery for reasons other than polyposis (control group). The serum zinc level was determined.ResultsThe mean age of the patients was 39.4 ± 12.61 years. Forty‐one patients (39%) were female. Based on the enzyme linked immunosorbent assay results, the average serum zinc level in the control group was 137.01 ± 19.42 (μgm/100 mL), and in all patients with CRSwNP, it was 127.27 ± 21.7 (μgm/100 mL). The serum zinc concentration in patients with CRSwNP was significantly lower than that in the control group (p = .027). Among the CRSwNP patients with eosinophilic polyps and neutrophilic polyps, 130.42 ± 21.92 (μgm/100 mL) and 127.27 ± 21.7 (μgm/100 mL), respectively, were detected. Based on the statistical analysis, the neutrophilic and eosinophilic groups were homogenous according to the average serum zinc concentration (p = .631), and the same conditions prevailed for the eosinophilic and control groups (p = .574). There was a noticeable distinction between the neutrophilic group and the control group (p = .034).ConclusionSerum zinc concentrations were significantly lower in patients with neutrophilic polyps than in the general population. This difference may be due to the essential role of zinc in the inflammatory process in patients with neutrophilic polyposis.

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Metallothionein-3 is a clinical biomarker for tissue zinc levels in nasal mucosa

Cited by 4 publications

References 33 publications

Protein interactions with metallothionein-3 promote vectorial active transport in human proximal tubular cells

Protein interactions with metallothionein-3 promote vectorial active transport in human proximal tubular cells

Remodeling of Paranasal Sinuses Mucosa Functions in Response to Biofilm-Induced Inflammation

Comparison of serum zinc levels between patients with sinonasal neutrophilic and eosinophilic inflammatory polyposis and healthy individuals

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