TRIM63
E3 ubiquitin-protein ligase TRIM63, also known as "MuRF1" (Muscle Ring-Finger Protein-1),[5] is an enzyme that in humans is encoded by the TRIM63 gene.[6][7][8]
| TRIM63 | |||||||||||||||||||||||||||||||||||||||||||||||||||
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| Aliases | TRIM63, IRF, MURF1, MURF2, RNF28, SMRZ, tripartite motif containing 63 | ||||||||||||||||||||||||||||||||||||||||||||||||||
| External IDs | OMIM: 606131 MGI: 2447992 HomoloGene: 41878 GeneCards: TRIM63 | ||||||||||||||||||||||||||||||||||||||||||||||||||
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This gene encodes a member of the RING zinc finger protein family found in striated muscle and iris. The product of this gene is localized to the Z-line and M-line lattices of myofibrils, where titin's N-terminal and C-terminal regions respectively bind to the sarcomere. In vitro binding studies have shown that this protein also binds directly to titin near the region of titin containing kinase activity. Another member of this protein family binds to microtubules. Since these family members can form heterodimers, this suggests that these proteins may serve as a link between titin kinase and microtubule-dependent signal pathways in muscle.[8]
The protein encoded by the Trim63 gene is also called MuRF1. MuRF1 is the name most commonly used in the literature, and it stands for "Muscle RING Finger 1." Structurally, there are two closely related MuRFs, MuRF2 and MuRF3. These also have TRIM codes: MuRF2 is TRIM55; MuRF3 is TRIM54.
Interactions
Trim63/MuRF1 has been shown to be an E3 ubiquitin ligase. Its major substrate is Myosin Heavy Chain (MHC, or Myosin-2, or MYH2), meaning it induces the proteasome-mediated degradatin of MHC, by causing MHC to be ubiquitinated.[9] MuRF1 is upregulated during skeletal muscle atrophy – and thus the degradation of myosin heavy chain, which is a major component of the sarcomere, is an important mechanism in the breakdown of skeletal muscle under atrophy conditions [5] MuRF1 has been shown to be upregulated during denervation, administration of glucocorticoids, immobilization, and casting (when a cast is applied to a limb, in order to immobilize it). All of these settings cause skeletal muscle atrophy.
TRIM63/MuRF1 has been shown to interact with Titin,[6] GMEB1[10] and SUMO2.[7]
Regulation during skeletal muscle atrophy
During settings of skeletal muscle atrophy, the levels of Trim63/MuRF1 mRNA increase. [5], leading to breakdown of the sarcomere.
This was found to be due to regulation of gene expression of Trim63/MuRF1 by the FOXO (or Forkhead) family of transcription factors. [11] ; see also FOX proteins.
Foxo1 or Foxo3 may regulate MuRF1. These factors are normally kept out of the nucleus by phosphorylation induced by a kinase called Akt. When Akt is inactivated, or less active, Foxo1 or Foxo3 can then transport to the nucleus, and induce expression of MuRF1.
Clinical significance
Recently, it has been suggested that TRIM63/MuRF1 is associated with an autosomal-recessive form of hypertrophic cardiomyopathy (HCM).[12] In this paper, the authors describe that individuals harboring homozygous or compound heterozygous rare variants in TRIM63/MuRF1 show a peculiar HCM phenotype, characterized by concentric left ventricular (LV) hypertrophy (50% of patients) and a high rate of LV dysfunction (20%). This finding suggests that Myosin Heavy Chain levels may be dysregulated in the heart in the absence of MuRF1, leading to pathology.
Upregulation of MuRF1/Trim63 mRNA is regularly used as an indicator that active skeletal muscle atrophy is occurring.
References
- GRCh38: Ensembl release 89: ENSG00000158022 - Ensembl, May 2017
- GRCm38: Ensembl release 89: ENSMUSG00000028834 - Ensembl, May 2017
- "Human PubMed Reference:". National Center for Biotechnology Information, U.S. National Library of Medicine.
- "Mouse PubMed Reference:". National Center for Biotechnology Information, U.S. National Library of Medicine.
- Bodine SC, Latres E, Baumhueter S, Lai VK, Nunez L, Clarke BA, Poueymirou WT, Panaro FJ, Na E, Dharmarajan K, Pan ZQ, Valenzuela DM, DeChiara TM, Stitt TN, Yancopoulos GD, Glass DJ (November 2001). "Identification of ubiquitin ligases required for skeletal muscle atrophy". Science. 294 (5547): 1704–1708. Bibcode:2001Sci...294.1704B. doi:10.1126/science.1065874. PMID 11679633. S2CID 37349291.
- Centner T, Yano J, Kimura E, McElhinny AS, Pelin K, Witt CC, Bang ML, Trombitas K, Granzier H, Gregorio CC, Sorimachi H, Labeit S (March 2001). "Identification of muscle specific ring finger proteins as potential regulators of the titin kinase domain". Journal of Molecular Biology. 306 (4): 717–726. doi:10.1006/jmbi.2001.4448. PMID 11243782.
- Dai KS, Liew CC (June 2001). "A novel human striated muscle RING zinc finger protein, SMRZ, interacts with SMT3b via its RING domain". The Journal of Biological Chemistry. 276 (26): 23992–23999. doi:10.1074/jbc.M011208200. PMID 11283016.
- "Entrez Gene: TRIM63 tripartite motif-containing 63".
- Clarke BA, Drujan D, Willis MS, Murphy LO, Corpina RA, Burova E, Rakhilin SV, Stitt TN, Patterson C, Latres E, Glass DJ (November 2007). "The E3 Ligase MuRF1 degrades myosin heavy chain protein in dexamethasone-treated skeletal muscle". Cell Metabolism. 6 (5): 376–385. doi:10.1016/j.cmet.2007.09.009. PMID 17983583.
- McElhinny AS, Kakinuma K, Sorimachi H, Labeit S, Gregorio CC (April 2002). "Muscle-specific RING finger-1 interacts with titin to regulate sarcomeric M-line and thick filament structure and may have nuclear functions via its interaction with glucocorticoid modulatory element binding protein-1". The Journal of Cell Biology. 157 (1): 125–136. doi:10.1083/jcb.200108089. PMC 2173255. PMID 11927605.
- Stitt TN, Drujan D, Clarke BA, Panaro F, Timofeyva Y, Kline WO, Gonzalez M, Yancopoulos GD, Glass DJ (May 2004). "The IGF-1/PI3K/Akt pathway prevents expression of muscle atrophy-induced ubiquitin ligases by inhibiting FOXO transcription factors". Molecular Cell. 14 (3): 395–403. doi:10.1016/s1097-2765(04)00211-4. PMID 15125842.
- Salazar-Mendiguchía J, Ochoa JP, Palomino-Doza J, Domínguez F, Díez-López C, Akhtar M, Ramiro-León S, Clemente MM, Pérez-Cejas A, Robledo M, Gómez-Díaz I, Peña-Peña ML, Climent V, Salmerón-Martínez F, Hernández C, García-Granja PE, Mogollón MV, Cárdenas-Reyes I, Cicerchia M, García-Giustiniani D, Lamounier A, Gil-Fournier B, Díaz-Flores F, Salguero R, Santomé L, Syrris P, Olivé M, García-Pavía P, Ortiz-Genga M, Elliott PM, Monserrat L (September 2020). "Mutations in TRIM63 cause an autosomal-recessive form of hypertrophic cardiomyopathy". Heart. 106 (17): 1342–1348. doi:10.1136/heartjnl-2020-316913. PMC 7476281. PMID 32451364.
Further reading
- Bodine SC, Latres E, Baumhueter S, Lai VK, Nunez L, Clarke BA, Poueymirou WT, Panaro FJ, Na E, Dharmarajan K, Pan ZQ, Valenzuela DM, DeChiara TM, Stitt TN, Yancopoulos GD, Glass DJ (November 2001). "Identification of ubiquitin ligases required for skeletal muscle atrophy". Science. 294 (5547): 1704–1708. Bibcode:2001Sci...294.1704B. doi:10.1126/science.1065874. PMID 11679633. S2CID 37349291.
- McElhinny AS, Kakinuma K, Sorimachi H, Labeit S, Gregorio CC (April 2002). "Muscle-specific RING finger-1 interacts with titin to regulate sarcomeric M-line and thick filament structure and may have nuclear functions via its interaction with glucocorticoid modulatory element binding protein-1". The Journal of Cell Biology. 157 (1): 125–136. doi:10.1083/jcb.200108089. PMC 2173255. PMID 11927605.
- Wistow G, Bernstein SL, Ray S, Wyatt MK, Behal A, Touchman JW, Bouffard G, Smith D, Peterson K (June 2002). "Expressed sequence tag analysis of adult human iris for the NEIBank Project: steroid-response factors and similarities with retinal pigment epithelium". Molecular Vision. 8: 185–195. PMID 12107412.
- Pizon V, Iakovenko A, Van Der Ven PF, Kelly R, Fatu C, Fürst DO, Karsenti E, Gautel M (December 2002). "Transient association of titin and myosin with microtubules in nascent myofibrils directed by the MURF2 RING-finger protein". Journal of Cell Science. 115 (Pt 23): 4469–4482. doi:10.1242/jcs.00131. PMID 12414993.
- Kedar V, McDonough H, Arya R, Li HH, Rockman HA, Patterson C (December 2004). "Muscle-specific RING finger 1 is a bona fide ubiquitin ligase that degrades cardiac troponin I". Proceedings of the National Academy of Sciences of the United States of America. 101 (52): 18135–18140. doi:10.1073/pnas.0404341102. PMC 539735. PMID 15601779.
- Witt SH, Granzier H, Witt CC, Labeit S (July 2005). "MURF-1 and MURF-2 target a specific subset of myofibrillar proteins redundantly: towards understanding MURF-dependent muscle ubiquitination". Journal of Molecular Biology. 350 (4): 713–722. doi:10.1016/j.jmb.2005.05.021. PMID 15967462.
- Doucet M, Russell AP, Léger B, Debigaré R, Joanisse DR, Caron MA, LeBlanc P, Maltais F (August 2007). "Muscle atrophy and hypertrophy signaling in patients with chronic obstructive pulmonary disease". American Journal of Respiratory and Critical Care Medicine. 176 (3): 261–269. doi:10.1164/rccm.200605-704OC. PMID 17478621.