PSMD14

PSMD14
Identifiers
Aliases	PSMD14, PAD1, POH1, RPN11, proteasome 26S subunit, non-ATPase 14
External IDs	MGI: 1913284 HomoloGene: 4240 GeneCards: PSMD14
Gene ontology Molecular function • metal ion binding • endopeptidase activator activity • proteasome binding • peptidase activity • protein binding • hydrolase activity • metallopeptidase activity Cellular component • cytosol • proteasome accessory complex • nucleoplasm • cytosolic proteasome complex • proteasome regulatory particle, lid subcomplex • proteasome complex • extracellular exosome • nucleus Biological process • regulation of proteasomal protein catabolic process • regulation of cellular amino acid metabolic process • antigen processing and presentation of exogenous peptide antigen via MHC class I, TAP-dependent • ubiquitin-dependent protein catabolic process • regulation of mRNA stability • positive regulation of canonical Wnt signaling pathway • protein polyubiquitination • stimulatory C-type lectin receptor signaling pathway • tumor necrosis factor-mediated signaling pathway • MAPK cascade • proteolysis • cellular response to DNA damage stimulus • Fc-epsilon receptor signaling pathway • protein K63-linked deubiquitination • NIK/NF-kappaB signaling • double-strand break repair via homologous recombination • negative regulation of ubiquitin-protein ligase activity involved in mitotic cell cycle • anaphase-promoting complex-dependent catabolic process • response to ethanol • double-strand break repair via nonhomologous end joining • T cell receptor signaling pathway • positive regulation of ubiquitin-protein ligase activity involved in regulation of mitotic cell cycle transition • negative regulation of canonical Wnt signaling pathway • DNA repair • positive regulation of endopeptidase activity • Wnt signaling pathway, planar cell polarity pathway • proteasome-mediated ubiquitin-dependent protein catabolic process Sources:Amigo / QuickGO
RNA expression pattern
More reference expression data
Orthologs
Species	Human	Mouse
Entrez	10213	59029
Ensembl	ENSG00000115233	ENSMUSG00000026914
UniProt	O00487	O35593
RefSeq (mRNA)	NM_005805	NM_021526
RefSeq (protein)	NP_005796.1	NP_067501.2
Location (UCSC)	Chr 2: 161.31 – 161.41 Mb	Chr 2: 61.71 – 61.8 Mb
PubMed search	[1]	[2]
Wikidata

26S proteasome non-ATPase regulatory subunit 14, also known as 26S proteasome non-ATPase subunit Rpn11, is an enzyme that in humans is encoded by the PSMD14 gene.^[3][4] This protein is one of the 19 essential subunits of a complete assembled 19S proteasome complex.^[5] Nine subunits Rpn3, Rpn5, Rpn6, Rpn7, Rpn8, Rpn9, Rpn11, SEM1(Yeast analogue for human protein DSS1), and Rpn12 form the lid sub complex of 19S regulatory particle for proteasome complex.^[5]

Gene

The gene PSMD14 encodes one of 26S proteasome non-ATPase subunit.^[4] The human gene PSMD14 has 12 Exons and locates at chromosome band 2q24.2.

Protein

The human protein 26S proteasome non-ATPase regulatory subunit 14 is 34.6 kDa in size and composed of 310 amino acids. The calculated theoretical pI of this protein is 6.06.^[6]

Complex assembly

26S proteasome complex is usually consisted of a 20S core particle (CP, or 20S proteasome) and one or two 19S regulatory particles (RP, or 19S proteasome) on either one side or both side of the barrel-shaped 20S. The CP and RPs pertain distinct structural characteristics and biological functions. In brief, 20S sub complex presents three types proteolytic activities, including caspase-like, trypsin-like, and chymotrypsin-like activities. These proteolytic active sites located in the inner side of a chamber formed by 4 stacked rings of 20S subunits, preventing random protein-enzyme encounter and uncontrolled protein degradation. The 19S regulatory particles can recognize ubiquitin-labeled protein as degradation substrate, unfold the protein to linear, open the gate of 20S core particle, and guide the substate into the proteolytic chamber. To meet such functional complexity, 19S regulatory particle contains at least 18 constitutive subunits. These subunits can be categorized into two classes based on the ATP dependence of subunits, ATP-dependent subunits and ATP-independent subunits. According to the protein interaction and topological characteristics of this multisubunit complex, the 19S regulatory particle is composed of a base and a lid subcomplex. The base consists of a ring of six AAA ATPases (Subunit Rpt1-6, systematic nomenclature) and four non-ATPase subunits (Rpn1, Rpn2, Rpn10, and Rpn13).s The lid sub complex of 19S regulatory particle consisted of 9 subunits. The assembly of 19S lid is independent to the assembly process of 19S base. Two assembly modules, Rpn5-Rpn6-Rpn8-Rpn9-Rpn11 modules and Rpn3-Rpn7-SEM1 modules were identified during 19S lid assembly using yeast proteasome as a model complex.^{[7][8][9][10]} The subunit Rpn12 incorporated into 19S regulatory particle when 19S lid and base bind together.^[11] Among these lid subunits, protein Rpn11 presents the metalloproteases activity to hydrolyze the ubiquitin molecules from the poly-ubiquitin chain before protein substrates are unfolded and degraded.^[12][13] During substrate degradation, the 19S regulatory particles undergo a conformation switch that is characterized by a rearranged ATPase ring with uniform subunit interfaces. Notably, Rpn11 migrates from an occluded position to directly above the central pore, thus facilitating substrate deubiquitination concomitant with translocation.^[14]

Function

As the degradation machinery that is responsible for ~70% of intracellular proteolysis,^[15] proteasome complex (26S proteasome) plays a critical roles in maintaining the homeostasis of cellular proteome. Accordingly, misfolded proteins and damaged protein need to be continuously removed to recycle amino acids for new synthesis; in parallel, some key regulatory proteins fulfill their biological functions via selective degradation; furthermore, proteins are digested into peptides for MHC class I antigen presentation. To meet such complicated demands in biological process via spatial and temporal proteolysis, protein substrates have to be recognized, recruited, and eventually hydrolyzed in a well controlled fashion. Thus, 19S regulatory particle pertains a series of important capabilities to address these functional challenges. To recognize protein as designated substrate, 19S complex has subunits that are capable to recognize proteins with a special degradative tag, the ubiquitinylation. It also have subunits that can bind with nucleotides (e.g., ATPs) in order to facilitate the association between 19S and 20S particles, as well as to cause confirmation changes of alpha subunit C-terminals that form the substate entrance of 20S complex. Protein Rpn11 presents the metalloproteases activity to hydrolyze the ubiquitin molecules from the poly-ubiquitin chain before protein substrates are unfolded and degraded^[12]

Clinical significance

The Proteasome and its subunits are of clinical significance for at least two reasons: (1) a compromised complex assembly or a dysfunctional proteasome can be associated with the underlying pathophysiology of specific diseases, and (2) they can be exploited as drug targets for therapeutic interventions. More recently, more effort has been made to consider the proteasome for the development of novel diagnostic markers and strategies. An improved and comprehensive understanding of the pathophysiology of the proteasome should lead to clinical applications in the future.

The proteasomes form a pivotal component for the Ubiquitin-Proteasome System (UPS) ^[16] and corresponding cellular Protein Quality Control (PQC). Protein ubiquitination and subsequent proteolysis and degradation by the proteasome are important mechanisms in the regulation of the cell cycle, cell growth and differentiation, gene transcription, signal transduction and apoptosis.^[17] Subsequently, a compromised proteasome complex assembly and function lead to reduced proteolytic activities and the accumulation of damaged or misfolded protein species. Such protein accumulation may contribute to the pathogenesis and phenotypic characteristics in neurodegenerative diseases,^[18][19] cardiovascular diseases,^[20][21][22] inflammatory responses and autoimmune diseases,^[23] and systemic DNA damage responses leading to malignancies.^[24]

Several experimental and clinical studies have indicated that aberrations and deregulations of the UPS contribute to the pathogenesis of several neurodegenerative and myodegenerative disorders, including Alzheimer's disease,^[25] Parkinson's disease^[26] and Pick's disease,^[27] Amyotrophic lateral sclerosis (ALS),^[27] Huntington's disease,^[26] Creutzfeldt–Jakob disease,^[28] and motor neuron diseases, polyglutamine (PolyQ) diseases, Muscular dystrophies^[29] and several rare forms of neurodegenerative diseases associated with dementia.^[30] As part of the Ubiquitin-Proteasome System (UPS), the proteasome maintains cardiac protein homeostasis and thus plays a significant role in cardiac Ischemic injury,^[31] ventricular hypertrophy^[32] and Heart failure.^[33] Additionally, evidence is accumulating that the UPS plays an essential role in malignant transformation. UPS proteolysis plays a major role in responses of cancer cells to stimulatory signals that are critical for the development of cancer. Accordingly, gene expression by degradation of transcription factors, such as p53, c-Jun, c-Fos, NF-κB, c-Myc, HIF-1α, MATα2, STAT3, sterol-regulated element-binding proteins and androgen receptors are all controlled by the UPS and thus involved in the development of various malignancies.^[34] Moreover, the UPS regulates the degradation of tumor suppressor gene products such as adenomatous polyposis coli (APC) in colorectal cancer, retinoblastoma (Rb). and von Hippel-Lindau tumor suppressor (VHL), as well as a number of proto-oncogenes (Raf, Myc, Myb, Rel, Src, Mos, Abl). The UPS is also involved in the regulation of inflammatory responses. This activity is usually attributed to the role of proteasomes in the activation of NF-κB which further regulates the expression of pro inflammatory cytokines such as TNF-α, IL-β, IL-8, adhesion molecules (ICAM-1, VCAM-1, P selectine) and prostaglandins and nitric oxide (NO).^[23] Additionally, the UPS also plays a role in inflammatory responses as regulators of leukocyte proliferation, mainly through proteolysis of cyclines and the degradation of CDK inhibitors.^[35] Lastly, autoimmune disease patients with SLE, Sjogren's syndrome and rheumatoid arthritis (RA) predominantly exhibit circulating proteasomes which can be applied as clinical biomarkers.^[36]

References

Further reading

External links

• PSMD14 human gene location in the UCSC Genome Browser.
• PSMD14 human gene details in the UCSC Genome Browser.