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BBA - Molecular Basis of Disease (v.1792, #3)

Editorial Board (pp. i).

Emerging roles of desumoylating enzymes by Jung Hwa Kim ⁎; Sung Hee Baek ⁎ (pp. 155-162).

Posttranslational modification by small ubiquitin-like modifier (SUMO) controls diverse cellular processes including transcriptional regulation, nuclear transport, cell-cycle progression, DNA repair, and signal transduction pathway. Sumoylation is a highly dynamic process that is reversed by a family of Sentrin/SUMO-specific proteases (SENPs). Thus, desumoylation process must be important for regulation of the fate and function of SUMO-conjugated proteins as well as SUMOylation process. SENPs catalyze the removal of SUMO from SUMO-conjugated target proteins as well as the cleavage of SUMO from its precursor proteins. Since the first report of yeast desumoylating enzymes, many studies have revealed the structural and cellular biological properties of SENP family. This review focuses on the specificity of the SENPs' catalytic activities with regard to SUMO isoforms and their emerging roles as cellular regulators.

Keywords: Desumoylation enzyme; SUMO; Ulp; SENP; SUMO isoform

Tumor necrosis factor alpha −308 gene locus promoter polymorphism: An analysis of association with health and disease by Maqsood M. Elahi; Kamlesh Asotra; Bashir M. Matata ⁎; Sarabjit S. Mastana (pp. 163-172).

Tumor necrosis factor-alpha (TNF-α) is a potent immunomediator and proinflammatory cytokine that has been implicated in the pathogenesis of a large number of human diseases. The location of its gene within major histocompatibility complex and biological activities has raised the possibility that polymorphisms within this locus may contribute to the pathogenesis of wide range of autoimmune and infectious diseases. For example, a bi-allelic single nucleotide substitution of G (TNFA1 allele) with A (TNFA2 allele)} polymorphism at −308 nucleotides upstream from the transcription initiation site in the TNF-α promoter is associated with elevated TNF-α levels and disease susceptibilities. However, it is still unclear whether TNF-α −308 polymorphism plays a part in the disease process, in particular whether it could affect transcription factor binding and in turn influence TNF-α transcription and synthesis. Several studies have suggested that TNFA2 allele is significantly linked with the high TNF-α-producing autoimmune MHC haplotype HLA-A1, B8, DR3, with elevated serum TNF-α levels and a more severe outcome in diseases. This review discusses the genetics of the TNF-α −308 polymorphism in selected major diseases and evaluates its common role in health and disease.

Keywords: Systemic inflammatory response; Inflammatory marker; Genetic; Cardiovascular disease; Cancer; Rheumatoid arthritis; Single nucleotide polymorphism

Chloride channelopathies by Rosa Planells-Cases; Thomas J. Jentsch ⁎ (pp. 173-189).

Channelopathies, defined as diseases that are caused by mutations in genes encoding ion channels, are associated with a wide variety of symptoms. Impaired chloride transport can cause diseases as diverse as cystic fibrosis, myotonia, epilepsy, hyperekplexia, lysosomal storage disease, deafness, renal salt loss, kidney stones and osteopetrosis. These disorders are caused by mutations in genes belonging to non-related gene families, i.e. CLC chloride channels and transporters, ABC transporters, and GABA- and glycine receptors. Diseases due to mutations in TMEM16E and bestrophin 1 might be due to a loss of Ca⁺⁺-activated Cl⁻ channels, although this remains to be shown.

Keywords: Bartter syndrome; CFTR; Dent's disease; Gnathodiaphyseal dysplasia; Macular dystrophy; Neuronal ceroid lipofuscinosis; NCL; Thomsen's disease

Lipid induced overexpression of NF-κB in skeletal muscle cells is linked to insulin resistance by Pomy Barma; Sushmita Bhattacharya; Anirban Bhattacharya; Rakesh Kundu; Suman Dasgupta; Anindita Biswas; Shelley Bhattacharya; Sib Sankar Roy; Samir Bhattacharya ⁎ (pp. 190-200).

Lipid induced NF-κB activation is known to be associated with insulin resistance and type2 diabetes. Here we show that incubation of L6 skeletal muscle cells with palmitate significantly increased NF-κB p65 and NF-κB p50 expression along with their phosphorylation. NF-κB p65 siRNA inhibited palmitate induced overexpression of NF-κB p65 indicating palmitate effect on transcriptional activation. RT-PCR and real time PCR experiments also showed a significant increase in NF-κB p65 gene expression due to palmitate. Overexpression of NF-κB p65 by palmitate was linked to impairment of insulin activity. Palmitate effect on NF-κB gene and protein expression was found to be mediated by phospho-PKCɛ as calphostin C (an inhibitor of PKC) and ɛV1 (PKCɛ translocation inhibitor) significantly reduced NF-κB expression. To understand the underlying mechanism, we purified NF-κB and pPKCɛ from palmitate incubated skeletal muscle cells and their interaction in cell free system demonstrated the transfer of phosphate from PKCɛ to NF-κB. This prompted us to transduct pPKCɛ to the skeletal muscle cells. These cells showed increased amount of pNF-κB and NF-κB. Excess of NF-κB p65 pool thus created in the cells made them insulin resistant. Addition of NF-κB p65 siRNA and SN50 inhibited palmitate induced NF-κB p65 expression indicating NF-κB regulation of its gene expression. Increase of NF-κB did not affect the activation of IKK/IκB indicating NF-κB p65 expression to be a distinct effect of palmitate. Since NF-κB p65 is linked to several diseases, including type2 diabetes, this report may be important in understanding the pathogenicity of these diseases.

Keywords: Insulin resistance; NF-κB; Free fatty acid; PKCɛ; Insulin signaling

A novel point mutation in the CYBB gene promoter leading to a rare X minus chronic granulomatous disease variant — Impact on the microbicidal activity of neutrophils by Federica Defendi; Eva Decleva; Cécile Martel; Pietro Dri; Marie José Stasia (pp. 201-210).

This article reports an atypical and extremely rare case of X-linked CGD in an Italian family characterized by a low expression of gp91 phox (X91⁻ CGD). A novel point mutation in the CYBB gene's promoter (insertion of a T at position −54T to −56T) appeared to prevent the full expression of this gene in the patient's neutrophils and correlated with a residual oxidase activity in the whole cells population. The expression and functional activity of the oxidase in eosinophils appeared to be almost normal. Gel shift assays indicated that the mutation led to decreased interactions with DNA-binding proteins. The total O₂⁻ production in the patient's granulocytes (5–7% of normal) supported no microbicidal power after 45 min and 60 min of contact with S. aureus and C. albicans, respectively. Despite this residual oxidase activity, the patients suffered from severe and life-threatening infections. It was concluded that in these X91⁻ CGD neutrophils, the O₂⁻ production per se was not sufficient to protect the patient against severe infections.

Keywords: Chronic granulomatous disease; CYBB; gene promoter; Point mutation; Cytochrome; b; ₅₅₈; NADPH oxidase; Microbicidal activity

Distinct roles for AF-1 and -2 of ER-alpha in regulation of MMP-13 promoter activity by Yamini Achari; Ting Lu; Benita S. Katzenellenbogen; David A. Hart ⁎ (pp. 211-220).

Previous studies have indicated that ER-α can influence the activity of the MMP-13 promoter. ER-α activity is mediated by two separate transcriptional activation domains (AF-1 and AF-2). The present study focused on analyzing the roles of these domains on the activation of the MMP-13 promoter. Transfection of synoviocytes with an ER-α construct lacking the C-terminus AF-2 domain led to significant elevation in MMP-13 promoter activity compared to wild type ER-α. Progressive deletions in the N-terminal AF-1 domain led to significant losses in MMP-13 promoter activity. MMP-13 promoter mutagenesis indicated that an AP-1 regulatory site was essential for ER-α mutant activity. Thus, both AF-1 and AF-2 domains of ER-α are required for regulation of MMP-13 promoter activity. As ER variants and ER related proteins have been implicated in bone and joint disorders, these findings provide understanding of the possible role of ER variants in the development of such conditions.

Keywords: MMP-13; ER-α mutant; AF-1; AF-2; AP-1 Site; Gene regulation

Compensatory expression of human N-Acetylglucosaminyl-1-phosphotransferase subunits in mucolipidosis type III gamma by Sandra Pohl ⁎; Stephan Tiede; Monica Castrichini; Michael Cantz; Volkmar Gieselmann; Thomas Braulke (pp. 221-225).

The N-Acetylglucosaminyl-1-phosphotransferase plays a key role in the generation of mannose 6-phosphate (M6P) recognition markers essential for efficient transport of lysosomal hydrolases to lysosomes. The phosphotransferase is composed of six subunits (α₂, β₂, γ₂). The α- and β-subunits are catalytically active and encoded by a single gene, GNPTAB, whereas the γ-subunit encoded by GNPTG is proposed to recognize conformational structures common to lysosomal enzymes. Defects in GNPTG cause mucolipidosis type III gamma, which is characterized by missorting and cellular loss of lysosomal enzymes leading to lysosomal accumulation of storage material. Using plasmon resonance spectrometry, we showed that recombinant γ-subunit failed to bind the lysosomal enzyme arylsulfatase A. Additionally, the overexpression of the γ-subunit in COS7 cells did not result in hypersecretion of newly synthesized lysosomal enzymes expected for competition for binding sites of the endogenous phosphotransferase complex. Analysis of fibroblasts exhibiting a novel mutation in GNPTG (c.619insT, p.K207IfsX7) revealed that the expression of GNPTAB was increased whereas in γ-subunit overexpressing cells the GNPTAB mRNA was reduced. The data suggest that the γ-subunit is important for the balance of phosphotransferase subunits rather for general binding of lysosomal enzymes.

Keywords: Mucolipidosis type III; GNPTG; Mannose 6-phosphate; Sorting of lysosomal enzymes; GlcNAc-1-phosphotransferase

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BBA - Molecular Basis of Disease (v.1792, #3)