Tripartite motif-containing protein 32 is a protein that in humans is encoded by the TRIM32 gene. [5] [6] [7] [8] Since its discovery in 1995, TRIM32 has been shown to be implicated in a number of diverse biological pathways.
Tripartite motif-containing protein 32 is a protein that in humans is encoded by the TRIM32 gene. [5] [6] [7] [8] Since its discovery in 1995, TRIM32 has been shown to be implicated in a number of diverse biological pathways.
The protein encoded by this gene is a member of the tripartite motif (TRIM) family. The TRIM motif includes three zinc-binding domains, a RING, a B-box type 1 and a B-box type 2, and a coiled-coil region. [8]
The protein localizes to cytoplasmic bodies. The protein has also been localized to the nucleus, where it interacts with the activation domain of the HIV-1 Tat protein. The Tat protein activates transcription of HIV-1 genes. [8]
TRIM32 has been shown to interact with:
Currently, TRIM32 is believed to employ two different mechanisms to affect molecular targets. First, it can act through its N-terminal RING finger as an E3 ubiquitin ligase, responsible for attaching ubiquitin molecules to lysine residues of target proteins, in order to mark them for proteosome degradation. Currently evidence suggests TRIM32 ubiquitinates multiple proteins including c-Myc, dysbindin, actin, piasy, and Abl-interactor2 (ABI2). The second mechanism by which TRIM32 is believed to operate involves binding of proteins to the C-terminal NHL repeat, which has been shown to activate miRNAs. [11]
Research has recently shown the importance of TRIM32 in the development of the mouse neocortex. In the mouse neocortex, neural progenitor cells generate daughter cells which either differentiate into specific neurons or maintain the progenitor state of the mother cell. TRIM32 helps control the balance between differentiating and progenitor cells by localizing to a pole during progenitor cell division, and thus becoming concentrated in one of the two daughter cells. This asymmetric division of TRIM32 induces neuronal differentiation in daughter cells which contain high TRIM32 concentrations, while cells with low TRIM32 concentrations retain progenitor cell fate. Proposed theories on how TRIM32 induces differentiation involve the ubiquitination of the transcription factor c-Myc and the binding of Argonaute-1 (Ago-1). The binding of Ago-1 induces activity of miRNAs, particularly Let-7a, which has been shown to play a role in regulating proliferation and neuronal differentiation. [11]
TRIM32 is expressed in skeletal muscle, where it interacts with myosin and may ubiquitinate actin (it has been shown to do so in vitro). [9] No difference has been observed between wild-type and LHMD2H-mutated TRIM32 in terms of actin or myosin binding, however, and thus the mechanism which causes the muscular dystrophy, LGMD2H, is still unknown. [14] Additionally, TRIM32 is known to ubiquitinate dysbindin, a protein associated with both skeletal muscles and neural tissue. The purpose and effects of the ubiquitination of dysbindin are as yet unclear. [12]
Bardet–Biedl syndrome (BBS): TRIM32 is one of 14 [15] genes known to be linked with BBS. Specifically a mutation (P130S) in the B-box of TRIM32 gives rise to BBS. [12]
Limb-girdle muscular dystrophy type2H (LGMD2H): LGMD2H is caused by 4 mutations of TRIM32 in the C-terminal NHL domain: D487N (third NHL repeat), R394H (first NHL repeat), T520TfsX13 (fourth NHL repeat), and D588del (fifth NHL repeat). [12]
TRIM32 is overexpressed in skin cancer cells. It is thought that TRIM32 regulates NF-κB activity through ubiquitination of Protein Inhibitor of Activated STAT Y (Piasy). [13] Piasy acts as an inhibitor of NF-κB, and NF-κB acts as an anti-apoptotic factor. Thus, when Piasy is present, NF-κB is inhibited, and keratinocytes undergo apoptosis when exposed to ultraviolet-B radiation or TNFα, preventing cancer formation. When TRIM32 is overexpressed, Piasy is degraded, allowing NF-κB to function, and thus when cells are exposed to ultraviolet-B radiation or TNFα, apoptosis does not occur, potentially allowing cancer formation. [14]
TRIM32 additionally promotes cancer formation by ubiquitinating Abl-interactor 2 (Abi2), which is a tumor suppressor and inhibitor of cell migration. [13]
A ubiquitin ligase is a protein that recruits an E2 ubiquitin-conjugating enzyme that has been loaded with ubiquitin, recognizes a protein substrate, and assists or directly catalyzes the transfer of ubiquitin from the E2 to the protein substrate. In simple and more general terms, the ligase enables movement of ubiquitin from a ubiquitin carrier to another thing by some mechanism. The ubiquitin, once it reaches its destination, ends up being attached by an isopeptide bond to a lysine residue, which is part of the target protein. E3 ligases interact with both the target protein and the E2 enzyme, and so impart substrate specificity to the E2. Commonly, E3s polyubiquitinate their substrate with Lys48-linked chains of ubiquitin, targeting the substrate for destruction by the proteasome. However, many other types of linkages are possible and alter a protein's activity, interactions, or localization. Ubiquitination by E3 ligases regulates diverse areas such as cell trafficking, DNA repair, and signaling and is of profound importance in cell biology. E3 ligases are also key players in cell cycle control, mediating the degradation of cyclins, as well as cyclin dependent kinase inhibitor proteins. The human genome encodes over 600 putative E3 ligases, allowing for tremendous diversity in substrates.
Protein inhibitor of activated STAT (PIAS), also known as E3 SUMO-protein ligase PIAS, is a protein that regulates transcription in mammals. PIAS proteins act as transcriptional co-regulators with at least 60 different proteins in order to either activate or repress transcription. The transcription factors STAT, NF-κB, p73, and p53 are among the many proteins that PIAS interacts with.
ITCH is a HECT domain E3 ubiquitin ligase that is ablated in non-agouti-lethal 18H mice. Itchy mice develop a severe immunological phenotype after birth that includes hyperplasia of lymphoid and hematopoietic cells, and stomach and lung inflammation. In humans ITCH deficiency causes altered physical growth, craniofacial morphology defects, defective muscle development, and aberrant immune system function. ITCH contains a C2 domain, proline-rich region, WW domains, HECT domain, and multiple amino acids that are phosphorylated and ubiquitinated.
Dynactin subunit 1 is a protein that in humans is encoded by the DCTN1 gene.
E3 ubiquitin-protein ligase NEDD4, also known as neural precursor cell expressed developmentally down-regulated protein 4 is an enzyme that is, in humans, encoded by the NEDD4 gene.
Calpain-3 is a protein that in humans is encoded by the CAPN3 gene.
F-box/WD repeat-containing protein 7 is a protein that in humans is encoded by the FBXW7 gene.
Ubiquitin-conjugating enzyme E2 L3 (UBE2L3), also called UBCH7, is a protein that in humans is encoded by the UBE2L3 gene. As an E2 enzyme, UBE2L3 participates in ubiquitination to target proteins for degradation. The role of UBE2L3 in the ubiquitination of the NF-κB precursor implicated it in various major autoimmune diseases, including rheumatoid arthritis (RA), celiac disease, Crohn's disease (CD), and systemic lupus erythematosus.
Delta-sarcoglycan is a protein that in humans is encoded by the SGCD gene.
Ubiquitin-conjugating enzyme E2 D2 is a protein that in humans is encoded by the UBE2D2 gene.
E3 ubiquitin-protein ligase HUWE1 is an enzyme that in humans is encoded by the HUWE1 gene.
Myotilin is a protein that in humans is encoded by the MYOT gene. Myotilin also known as TTID is a muscle protein that is found within the Z-disc of sarcomeres.
Tripartite motif-containing protein 37 is an E3 ubiquitin ligase in humans that is encoded by the TRIM37 gene.
The human gene UBR1 encodes the enzyme ubiquitin-protein ligase E3 component n-recognin 1.
Midline-2 is a protein that in humans is encoded by the MID2 gene.
Tripartite motif-containing 22, also known as TRIM22, is a protein which in humans is encoded by the TRIM22 gene.
E3 ubiquitin-protein ligase MARCH2 is an enzyme that in humans is encoded by the MARCH2 gene. It is a member of the MARCH family of E3 ligases, and plays an important role in the turnover of membrane proteins. MARCH2 has been shown to negatively regulate NF-κB essential modulator function upon viral and bacterial infections.
Chaperone-assisted selective autophagy is a cellular process for the selective, ubiquitin-dependent degradation of chaperone-bound proteins in lysosomes.
Mitochondrial E3 ubiquitin protein ligase 1 (MUL1) is an enzyme that in humans is encoded by the MUL1 gene on chromosome 1. This enzyme localizes to the outer mitochondrial membrane, where it regulates mitochondrial morphology and apoptosis through multiple pathways, including the Akt, JNK, and NF-κB. Its proapoptotic function thus implicates it in cancer and Parkinson’s disease.
Probable E3 ubiquitin-protein ligase HERC3 is an enzyme that in humans is encoded by the HERC3 gene. The gene is a member of the HERC family of ubiquitin ligases and encodes a protein with a HECT domain and an RCC1-like domain (RLD). It binds ubiquitin and hPLIC-1/2 via its HECT domain. Alternatively spiced transcript variants encoding multiple isoforms have been observed, and mutations in this gene have been linked to colorectal and gastric carcinomas. The protein is localized in the cytosol and vesicular-like structures containing β-COP, ARF, and Rab5. Since HERC3 can itself be ubiquitinated and degraded by the proteasome, it likely has roles in both vesicular traffic and ubiquitin-dependent processes.