TRIM63 explained

E3 ubiquitin-protein ligase TRIM63, also known as "MuRF1" (Muscle Ring-Finger Protein-1),^[1] is an enzyme that in humans is encoded by the TRIM63 gene.^{[2] [3] [4]}

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.

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 degradation of MHC, by causing MHC to be ubiquitinated.^[5] 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 ^[1] 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, GMEB1^[6] and SUMO2.

Regulation during skeletal muscle atrophy

During settings of skeletal muscle atrophy, the levels of Trim63/MuRF1 mRNA increase.,^[1] 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.;^[7] 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).^[8] 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.

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 . Identification of ubiquitin ligases required for skeletal muscle atrophy . Science . 294 . 5547 . 1704–1708 . November 2001 . 11679633 . 10.1126/science.1065874 . 37349291 . 2001Sci...294.1704B . free .
• McElhinny AS, Kakinuma K, Sorimachi H, Labeit S, Gregorio CC . 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 . April 2002 . 11927605 . 2173255 . 10.1083/jcb.200108089 .
• Wistow G, Bernstein SL, Ray S, Wyatt MK, Behal A, Touchman JW, Bouffard G, Smith D, Peterson K . 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 . June 2002 . 12107412 .
• Pizon V, Iakovenko A, Van Der Ven PF, Kelly R, Fatu C, Fürst DO, Karsenti E, Gautel M . 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 . December 2002 . 12414993 . 10.1242/jcs.00131 . 16068484 .
• Kedar V, McDonough H, Arya R, Li HH, Rockman HA, Patterson C . 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 . December 2004 . 15601779 . 539735 . 10.1073/pnas.0404341102 . free . 2004PNAS..10118135K .
• Witt SH, Granzier H, Witt CC, Labeit S . 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 . July 2005 . 15967462 . 10.1016/j.jmb.2005.05.021 .
• Doucet M, Russell AP, Léger B, Debigaré R, Joanisse DR, Caron MA, LeBlanc P, Maltais F . Muscle atrophy and hypertrophy signaling in patients with chronic obstructive pulmonary disease . American Journal of Respiratory and Critical Care Medicine . 176 . 3 . 261–269 . August 2007 . 17478621 . 10.1164/rccm.200605-704OC .

Notes and References

1. 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 . Identification of ubiquitin ligases required for skeletal muscle atrophy . Science . 294 . 5547 . 1704–1708 . November 2001 . 11679633 . 10.1126/science.1065874 . 37349291 . 2001Sci...294.1704B . free .
2. Centner T, Yano J, Kimura E, McElhinny AS, Pelin K, Witt CC, Bang ML, Trombitas K, Granzier H, Gregorio CC, Sorimachi H, Labeit S . Identification of muscle specific ring finger proteins as potential regulators of the titin kinase domain . Journal of Molecular Biology . 306 . 4 . 717–726 . March 2001 . 11243782 . 10.1006/jmbi.2001.4448 .
3. Dai KS, Liew CC . 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 . June 2001 . 11283016 . 10.1074/jbc.M011208200 . free .
4. Web site: Entrez Gene: TRIM63 tripartite motif-containing 63.
5. Clarke BA, Drujan D, Willis MS, Murphy LO, Corpina RA, Burova E, Rakhilin SV, Stitt TN, Patterson C, Latres E, Glass DJ . The E3 Ligase MuRF1 degrades myosin heavy chain protein in dexamethasone-treated skeletal muscle . Cell Metabolism . 6 . 5 . 376–385 . November 2007 . 17983583 . 10.1016/j.cmet.2007.09.009 . free .
6. McElhinny AS, Kakinuma K, Sorimachi H, Labeit S, Gregorio CC . 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 . April 2002 . 11927605 . 2173255 . 10.1083/jcb.200108089 .
7. Stitt TN, Drujan D, Clarke BA, Panaro F, Timofeyva Y, Kline WO, Gonzalez M, Yancopoulos GD, Glass DJ . 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 . May 2004 . 15125842 . 10.1016/s1097-2765(04)00211-4 . free .
8. 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 . Mutations in TRIM63 cause an autosomal-recessive form of hypertrophic cardiomyopathy . Heart . 106 . 17 . 1342–1348 . September 2020 . 32451364 . 7476281 . 10.1136/heartjnl-2020-316913 .