USP 3 (15q22.31) SIH003, UBP ( DUB- perheen alaryhmästä USP)

USP 3 (15q22.31) , SIH003, UBP

USP3 todettiin uudeksi deubikitinaasiksi vuonna 1999.

USP3 stabiloi p53-genomin suojelijan deubikitinoimalla (2017)

USP3 deubikitinoi RIG-1 ja virusinfektiossa myös RIG-1-kaltaiset (RLR) reseptorit ja täten inhibitoi tyypin 1 IFN-signalointia.

USP3 deubikitinaasi vastavaikuttaa RNF169 ring finger proteiinin tekemään ubikitiinin asettamiseen deubikitinoimalla H2A ja gammaH2AX K13 ja K15 lysiinikohdista. DNA vaurio vasteessa on olennaista näiden histonien ubikitinaatio RNF168 ja RNF3 E3 ubikitiiniligaaseilla ja niihin taas vastavaikuttaa USP3 ubikitiinisignaalin negatiivisella säätelyllä. USP3 poistaa Ub lysiineistä K13 ja K15 HXA ja gammaH2AX- histoneista sekä K118 ja K 119 H2AX- histonista DNA-vaurio vasteena.

USP3:n yliesiintymä UV tai gammasäteilyvaurioissa vaikuttaa alavirran säätelijöiden BRCA1 ja 53BP1 huonompaan kertymiseen vauriokohtaan .

Normaalisti USP3 pitoisuus on matala kudoksissa, korkein kuitenkin haimassa.

• https://www.ncbi.nlm.nih.gov/gene/9960

Also known as UBP; SIH003

Expression Ubiquitous expression in bone marrow (RPKM 9.8), spleen (RPKM 5.3) and 25 other tissues See more Orthologs mouse all

Related articles in PubMed

1. UCP3 polymorphisms, hand grip performance and survival at old age: association analysis in two Danish middle aged and elderly cohorts. Dato S, et al. Mech Ageing Dev, 2012 Aug. PMID 22743239, Free PMC Article Interestingly, we found that allele A at rs11235972, associated in this cohort with lowest HG scores, influences also the survival patterns, with people carrying this allele showing higher mortality rates. On the whole, our work supports the role of UCP3 gene in functional status and survival at old age.
2. USP3 stabilizes p53 protein through its deubiquitinase activity. Fu S, et al. Biochem Biophys Res Commun, 2017 Oct 14. PMID 28807825 p53 is the guardian of the genome integrity and the degradation of p53 protein is mediated by MDM2. Here we report that USP3 interacts with p53 and regulates p53 stability. Depletion of USP3 lead to accelerated degradation of p53 in normal cells thereby enhanced cell proliferation and transformation. Reconstitution of wildtype USP3, but not the USP3 C168S mutant, restored the stability of p53 protein and inhibited cell proliferation and transformation. These findings suggest that USP3 is an important regulator of p53 and regulates normal cell transformation.
3. Characterization and chromosomal localization of USP3, a novel human ubiquitin-specific protease. Sloper-Mould KE, et al. J Biol Chem, 1999 Sep 17. PMID 10480896 Conjugation to the small eukaryotic protein ubiquitin can functionally modify or target proteins for degradation by the proteasome. Removal of the ubiquitin modification, or deubiquitination, is performed by ubiquitin-specific proteases (USPs) and is an important mechanism regulating this pathway. Here we describe a novel human ubiquitin-specific protease, USP3, initially identified as a partial cDNA clone similar to one of two highly conserved sequence regions common to all ubiquitin-specific proteases. We have isolated a complete USP3 cDNA clone containing both of these conserved sequence regions. The USP3 gene appears to be single copy and maps to human chromosome 15q22.3. A USP3 probe detects two mRNA transcripts, one of which corresponds in length to the cDNA. Both are expressed at low levels in all tissues examined, with highest expression in pancreas. The USP3 protein is a functional ubiquitin-specific protease in vitro, and is able to inhibit ubiquitin-dependent degradation of both an N-end Rule substrate and abnormal endogenous proteins in yeast. USP3 is also only the second known ubiquitin-specific protease capable of efficiently cleaving a ubiquitin-proline bond.
4. USP3 inhibits type I interferon signaling by deubiquitinating RIG-I-like receptors. Cui J, et al. Cell Res, 2014 Apr. PMID 24366338, Free PMC Article Lysine 63 (K63)-linked ubiquitination of RIG-I plays a critical role in the activation of type I interferon pathway, yet the molecular mechanism responsible for its deubiquitination is still poorly understood. Here we report that the deubiquitination enzyme ubiquitin-specific protease 3 (USP3) negatively regulates the activation of type I interferon signaling by targeting RIG-I. We further show that there is no interaction between USP3 and RIG-I-like receptors (RLRs) in unstimulated or uninfected cells, but upon viral infection or ligand stimulation, USP3 binds to the caspase activation recruitment domain of RLRs and then cleaves polyubiquitin chains through cooperation of its RNF168 zinc-finger Ub-binding domain and USP catalytic domains. Mutation analysis reveals that binding of USP3 to polyubiquitin chains on RIG-I is a prerequisite step for its cleavage of polyubiquitin chains. Our findings identify a previously unrecognized role of USP3 in RIG-I activation and provide insights into the mechanisms by which USP3 inhibits RIG-I signaling and antiviral immunity.
5. USP3 counteracts RNF168 via deubiquitinating H2A and γH2AX at lysine 13 and 15. Sharma N, et al. Cell Cycle, 2014. PMID 24196443, Free PMC Article Abstract Histone ubiquitination plays a vital role in DNA damage response (DDR), which is important for maintaining genomic integrity in eukaryotic cells. In DDR, ubiquitination of histone H2A and γH2AX by the concerted action of ubiquitin (Ub) ligases, RNF168 and RNF8, generates a cascade of ubiquitination signaling. However, little is known about deubiquitinating enzymes (DUBs) that may catalyze the removal of Ub from these histones. This study demonstrated that USP3, an apparent DUB for mono-ubiquitinated H2A, is indeed the enzyme for deubiquitinating Ub conjugates of γH2AX and H2A from lysine sites, where the ubiquitination is initiated by RNF168. Here, we showed that ectopic expression of USP3 led to the deubiquitination of both H2A and γH2AX in response to UV-induced DNA damage. Moreover, ectopic USP3 expression abrogated FK2 antibody-reactive Ub-conjugate foci, which co-localize with damage-induced γH2AX foci. In addition, USP3 overexpression impaired the accumulation of downstream repair factors BRCA1 and 53BP1 at the damage sites in response to both UV and γ-irradiation. We further identified that the USP3 removes Ub at lysine 13 and 15 of H2A and γH2AX, as well as lysine 118 and 119 of H2AX in response to DNA damage. Taken together, the results suggested that USP3 is a negative regulator of ubiquitination signaling, counteracting RNF168- and RNF8-mediated ubiquitination.

See all (23) citations in PubMed
See citations in PubMed for homologs of this gene provided by HomoloGene

(Muistiin 1.7. 2018 , suomennosta myöhemmin)
 

Terminologiaa:

53BP1 (15q15.3) , function on DNA DSB repair, choise promoting NHEJ and limiting HR. Involved in V(D)J recombination, class switchrecombination and at unprotected telomeres. https://www.ncbi.nlm.nih.gov/gene/7158

Gamma radiation, ionizing radiation  

Histone

HXA

H2AX

gammaH1AX

Understanding HISTONE and DNA Damage ressponse . https://www.ncbi.nlm.nih.gov/pubmed/29858375

https://www.ncbi.nlm.nih.gov/pubmed/25305019

Interferons Type I

 IFN Type I, https://en.wikipedia.org/wiki/Interferon_type_I

 RIG- signalosome members  ( sensing viruses) 
 https://encrypted-tbn0.gstatic.com/images?q=tbn:ANd9GcSqGOduknGwmm4YyMF1nXk8BFl-zgNniqmcqnM86B9y6JcvolYa

RIG-1, ATP dependent RNA helicases DDX58, acid-inducible gene-I, (sensor) https://www.ncbi.nlm.nih.gov/protein/O95786.2

RLR.1, Rig-I-like receptor 1. (sensor)

RNF 168. Ring Zn Finger 168  https://www.ncbi.nlm.nih.gov/gene/165918

RNF8,  RING Zn Finger 8,  https://www.ncbi.nlm.nih.gov/gene/9025

UV, Ultraviolet radiation