Disease relevance of COMMD1

• Analysis of the human homologue of the canine copper toxicosis gene MURR1 in Wilson disease patients [1].

High impact information on COMMD1

• X-linked inhibitor of apoptosis (XIAP), known primarily for its caspase inhibitory properties, has recently been shown to interact with and regulate the levels of COMMD1, a protein associated with a form of canine copper toxicosis [2].
• COMMD1-deficient cells demonstrate stabilization of RelA, greater nuclear accumulation of RelA after TNF stimulation, de-repression of several kappaB-responsive genes, and enhanced NF-kappaB-mediated cellular responses [3].
• We report here that COMMD1 accelerates the ubiquitination and degradation of NF-kappaB subunits through its interaction with a multimeric ubiquitin ligase containing Elongins B and C, Cul2 and SOCS1 (ECS(SOCS1)) [3].
• XIAP was found to interact with MURR1, a factor recently implicated in copper homeostasis [4].
• However, cells and tissues derived from Xiap-deficient mice were found to contain reduced copper levels, while suppression of MURR1 resulted in increased intracellular copper in cultured cells [4].

Associations of COMMD1 with chemical compounds

• COMMD1 specifically binds phosphatidylinositol 4,5-bisphosphate (PtdIns(4,5)P2) in the absence of other proteins and does not bind structural lipids; the phosphorylation of PtdIns at position 4 is essential for COMMD1 binding [5].

Biological context of COMMD1

• COMMD proteins inhibit NFkappaB mediated gene expression, and recent mechanistic studies have revealed that COMMD1 controls the ubiquitination of NFkappaB subunits, an event linked to transcriptional termination [6].
• This review discusses how COMMD1 functions as a regulator of not only copper homeostasis but also sodium transport and the NF-kappaB signaling pathway [7].
• While screening genes and expressed sequence tags in this region for mutations we found that exon 2 of the MURR1 gene is deleted in both alleles of all affected Bedlington terriers and in single alleles in obligate carriers [8].
• Recent genetic data have revealed that MURR1, a single copy gene on dog chromosome 10q26, is mutated in this disorder [9].
• MURR1 is a multifunctional protein that inhibits nuclear factor kappaB (NF-kappaB), a transcription factor with pleiotropic functions affecting innate and adaptive immunity, apoptosis, cell cycle regulation, and oncogenesis [10].

Anatomical context of COMMD1

• MURR1 was also detected in different tissues and cell lines; in cell lines the protein was found both in cytosol and membrane preparations [11].

Regulatory relationships of COMMD1

• We found that ARF promotes the polyubiquitination of COMMD1 through Lys(63) of ubiquitin but not the polyubiquitination of Lys(48), which does not target COMMD1 for proteasome-dependent proteolysis [12].

Other interactions of COMMD1

• Studies of the underlying defects in ATP7B and its suspected modifiers ATOX1 and COMMD1 are expected to unravel the disease's genotype-phenotype correlation, and should lead to the design of improved drugs for ameliorating the suffering of patients [13].
• The three exons of the human MURR1 gene were sequenced after amplification of the genomic DNA by polymerase chain reaction.RESULTS: Our study did not reveal any mutations leading to an amino acid change in the MURR1 sequence of Wilson disease patients [14].

Analytical, diagnostic and therapeutic context of COMMD1

• METHODS: Polyclonal antibodies raised against full-length recombinant human MURR1 were used for immunoblot analysis and indirect immunofluorescence studies [11].
• RESULTS: Using Western blot analysis, these antibodies abundantly detected MURR1 as a 23 kDa protein in liver extracts of mice and dogs, but MURR1 was undetectable in the livers of affected Bedlington terriers [11].

References