Probable ubiquitin carboxyl-terminal hydrolase FAF-X is an enzyme that in humans is encoded by the USP9X gene. [5] [6]
Probable ubiquitin carboxyl-terminal hydrolase FAF-X is an enzyme that in humans is encoded by the USP9X gene. [5] [6]
This gene is a member of the peptidase C19 family and encodes a protein that is similar to ubiquitin-specific proteases. Though this gene is located on the X chromosome, it escapes X-inactivation.
Depletion of USP9X from two-cell mouse embryos halts blastocyst development and results in slower blastomere cleavage rate, impaired cell adhesion and a loss of cell polarity. It has also been implicated that USP9X is likely to influence developmental processes through signaling pathways of Notch, Wnt, EGF, and mTOR. USP9X has been recognized in studies of mouse and human stem cells involving embryonic, neural and hematopoietic stem cells. [7] High expression is retained in undifferentiated progenitor and stem cells and decreases as differentiation continues. USP9X is a protein-coding gene that has been implicated either directly through mutations or indirectly in a number of neurodevelopmental and neurodegenerative disorders. Three mutations have been connected with X-linked intellectual disability through disrupted neuronal growth and cell migration. Neurodegenerative disorders, such as Alzheimer's, Parkinson's and Huntington's disease, have also been linked to USP9X. Specifically, USP9X has been implicated in the regulation of the phosphorylation and expression of the microtule-associated protein tau, which forms pathological aggregates in Alzheimer's and other tauopathies. [8] Scientists have generated a knockout model where they isolated hippocampal neurons from an USP9X-knockout male mouse, which showed a 43% reduction in axonal length and arborization compared to wild type. [9]
USP9X has been shown to interact with:
Variants of the USP9X gene have been found to cause a neurodevelopmental USP9X syndrome in both males and females. USP9X is strongly evolutionarily conserved in humans and is intolerant to variation. This is due to the important role of the USP9X enzyme, which reverses protein ubiquitylation, thereby decreasing the enzymatic degradation and increasing the longevity of those proteins. [15] Being on the X chromosome, USP9X syndrome manifests differently in females compared to males. In females, loss of function variations in one copy of the gene results in haploinsufficiency. This is because USP9X escapes the usually-protective process of X-inactivation. As a result, even “carrier” females exhibit the syndrome.
Variants found in females with USP9X syndrome include whole or partial deletions of one copy of the USP9X gene, as well as mis-sense mutations or small in-frame deletion mutations. [15] Symptoms in females include intellectual disability, facial dysmorphia, and language impairment. Less common symptoms include short stature, scoliosis, polydactyly, and changes to dentition. [16] Females have a wider range of symptoms than males, likely due to their wider variety of USP9X gene variants compared to males. Other symptoms sometimes found in females but rarely or never in males include hip dysplasia, heart dysmorphia, hearing problems and abnormal skin pigmentation. [15]
USP9X variants seen in surviving males cause loss of function in brain-specific processes only, since total loss of function of this gene is fatal in the embryonic stage. Males are hemizygous for this gene because they possess only one X chromosome. Symptoms seen in affected males include intellectual disability, problems with language, speech, behaviour and sight, and facial dysmorphia. Specific brain abnormalities include white matter disturbances, a thin corpus callosum, and widened ventricles. [17]
Deubiquitinating enzymes (DUBs), also known as deubiquitinating peptidases, deubiquitinating isopeptidases, deubiquitinases, ubiquitin proteases, ubiquitin hydrolases, or ubiquitin isopeptidases, are a large group of proteases that cleave ubiquitin from proteins. Ubiquitin is attached to proteins in order to regulate the degradation of proteins via the proteasome and lysosome; coordinate the cellular localisation of proteins; activate and inactivate proteins; and modulate protein-protein interactions. DUBs can reverse these effects by cleaving the peptide or isopeptide bond between ubiquitin and its substrate protein. In humans there are nearly 100 DUB genes, which can be classified into two main classes: cysteine proteases and metalloproteases. The cysteine proteases comprise ubiquitin-specific proteases (USPs), ubiquitin C-terminal hydrolases (UCHs), Machado-Josephin domain proteases (MJDs) and ovarian tumour proteases (OTU). The metalloprotease group contains only the Jab1/Mov34/Mpr1 Pad1 N-terminal+ (MPN+) (JAMM) domain proteases.
Afadin is a protein that in humans is encoded by the AFDN gene.
Ubiquitin-specific-processing protease 7 (USP7), also known as ubiquitin carboxyl-terminal hydrolase 7 or herpesvirus-associated ubiquitin-specific protease (HAUSP), is an enzyme that in humans is encoded by the USP7 gene.
Ubiquitin carboxyl-terminal hydrolase 8 is an enzyme that in humans is encoded by the USP8 gene.
Ubiquitin carboxyl-terminal hydrolase 6 (USB6), also termed TRE17 and Tre-2, is a deubiquitinating enzyme that in humans is encoded by the hominid USP6 gene located at band 13.2 on the short arm of chromosome 17. Deubiquitinating enzymes (DUBs) are enzymes that act within cells to remove ubiquitins from various functionally important proteins. Ubiquitin enzymes add ubiquitin to these proteins and thereby regulate their cellular location, alter their activity, and/or promote their degradation. By deubiquitinating these proteins, DUBs counter the effects of the ubiquinating enzymes and contribute to regulating the actions of the targeted proteins. In normal adult tissues, USP6 is highly expressed in testicle tissue, modestly expressed in ovarian tissue, and absent or minimally expressed in other tissues. It is also highly expressed in fetal brain tissue. The specific functions of USP6 are poorly defined primarily because its presence is restricted to primates: there are no available animal models to determine the effects of its deletion, although some studies suggest that UPSP6 contributes to normal brain development. In all events, USP6 has gained wide interest because of its abnormally increased expression by the neoplastic cells in various tumors derived from mesenchymal tissue.
Ubiquitin specific peptidase 10, also known as USP10, is an enzyme which in humans is encoded by the USP10 gene.
Proteasomal ubiquitin receptor ADRM1 is a protein that in humans is encoded by the ADRM1 gene. Recent evidences on proteasome complex structure confirmed that the protein encoded by gene ADRM1, also known in yeast as 26S Proteasome regulatory subunit Rpn13, is a subunit of 19S proteasome complex.
Ubiquitin carboxyl-terminal hydrolase 16 is an enzyme that in humans is encoded by the USP16 gene.
Ubiquitin specific protease 4 (USP4) is an enzyme that cleaves ubiquitin from a number of protein substrates. Prior to the standardization of nomenclature USP4 was known as UNP, and was one of the first deubiquitinating enzymes to be identified in mammals. In the mouse and human the USP4 protein is encoded by a gene containing 22 exons.
Ubiquitin carboxyl-terminal hydrolase or Ubiquitin specific protease 11 is an enzyme that in humans is encoded by the USP11 gene. USP11 belongs to the Ubiquitin specific proteases family (USPs) which is a sub-family of the Deubiquitinating enzymes (DUBs).USPs are multiple domain proteases and belong to the C19 cysteine proteases sub‒family. Depending on their domain architecture and position there is different homology between the various members. Generally the largest domain is the catalytic domain which harbours the three residue catalytic triad that is included inside conserved motifs. The catalytic domain also contains sequences that are not related with the catalysis function and their role is mostly not clearly understood at present, the length of these sequences varies for each USP and therefore the length of the whole catalytic domain can range from approximately 295 to 850 amino acids. Particular sequences inside the catalytic domain or at the N‒terminus of some USPs have been characterised as UBL and DUSP domains respectively. In some cases, regarding the UBL domains, it has been reported to have a catalysis enhancing function as in the case of USP7. In addition, a so‒called DU domain module is the combination of a DUSP domain followed by a UBL domain separated by a linker and is found in USP11 as well as in USP15 and USP4.
Ubiquitin-specific protease 36 is an enzyme that in humans is encoded by the USP36 gene.
Ubiquitin carboxyl-terminal hydrolase 15 is an enzyme that in humans is encoded by the USP15 gene.
E3 ubiquitin-protein ligase NRDP1 is an enzyme that in humans is encoded by the RNF41 gene.
Ubiquitin carboxyl-terminal hydrolase 33 is an enzyme that in humans is encoded by the USP33 gene.
Ubiquitin-conjugating enzyme E2 J1 is a protein that in humans is encoded by the UBE2J1 gene.
Ubiquitin carboxyl-terminal hydrolase 48 is an enzyme that in humans is encoded by the USP48 gene.
Ubiquitin-specific protease 14 is an enzyme that in humans is encoded by the USP14 gene.
Ubiquitin carboxyl-terminal hydrolase 20 is an enzyme that in humans is encoded by the USP20 gene.
In Xenopus laevis, the specification of the three germ layers occurs at the blastula stage. Great efforts have been made to determine the factors that specify the endoderm and mesoderm. On the other hand, only a few examples of genes that are required for ectoderm specification have been described in the last decade. The first molecule identified to be required for the specification of ectoderm was the ubiquitin ligase Ectodermin ; later, it was found that the deubiquitinating enzyme, FAM/USP9x, is able to overcome the effects of ubiquitination made by Ectodermin in Smad4. Two transcription factors have been proposed to control gene expression of ectodermal specific genes: POU91/Oct3/4 and FoxIe1/Xema. A new factor specific for the ectoderm, XFDL156, has shown to be essential for suppression of mesoderm differentiation from pluripotent cells.
The ubiquitin carboxyl-terminal hydrolase 27, also known as deubiquitinating enzyme 27, ubiquitin thioesterase 27 and USP27X, is a deubiquitinating enzyme which is mainly characterized for cleaving ubiquitin (Ub) from proteins and other molecules. Ubiquitin binds to proteins so as to regulate the degradation of them via the proteasome and lysosome among many other functions.