• Source: RBCK1

RanBP-type and C3HC4-type zinc finger-containing protein 1 (also known as HOIL-1) is a protein that in humans is encoded by the RBCK1 gene.
The protein encoded by this gene is similar to mouse UIP28/UbcM4 interacting protein. Alternative splicing has been observed at this locus, resulting in distinct isoforms.
HOIL-1 is an E3 ubiquitin ligase and a part of the linear ubiquitin chain assembly complex (LUBAC), the only known ubiquitin ligase generating linear (Met1) polyubiquitin linkages. Although HOIL-1 isn’t responsible for the linear ubiquitin generation, it is a necessary component of LUBAC and ensures its proper assembly and function. Interestingly, unlike most E3 ubiquitin ligases, HOIL-1 is able to catalyze oxyester bond formation between the C-terminus of a ubiquitin monomer and Ser/Thr of a different protein. This recently discovered function of HOIL-1 has so far been described in the context of MyD88 signaling. Additionally, a catalytically inactive mutant of HOIL-1 (HOIL-1C458S) led to prolonged IKK activation and increase of inflammatory cytokine production by cytotoxic T cells. The proposed mechanism is that the ester-linked ubiquitin chains limit the size of isopeptide-linked (K63 and/or M1) ubiquitin chains.




Clinical significance


A family quartet was found with two children, both affected with a previously unreported disease, characterized by progressive muscular weakness and cardiomyopathy, with normal intelligence. During the course of the study, one additional unrelated patient was found with a comparable phenotype. From whole-genome sequence data, RBCK1, a gene encoding an E3 ubiquitin-protein ligase, was identified as the most likely candidate gene, with two protein-truncating mutations in probands in the first family. Sanger sequencing identified a private homozygous splice variant in RBCK1 in the proband in the second family, yet single-nucleotide polymorphism (SNP) genotyping revealed a 1.2Mb copy-neutral region of homozygosity covering RBCK1. RNA-Seq confirmed aberrant splicing of RBCK1 transcripts, resulting in truncated protein products. Ten other individuals with mutations in RBCK1 and overlapping phenotypes have been identified.




References






Further reading

Kata Kunci Pencarian:

• RBCK1
• List of human transcription factors
• List of human protein-coding genes 3
• RING finger domain
• Complete Genomics
• Shu Hongbing
• MALT1
• TRAF1