All known vertebrate TRIMs are
All known vertebrate TRIMs are categorized in 11 distinct subclasses depending on the types of domains present at their carboxyl-terminals (Fig. 3) , . Beyond conserved N-terminal domains, it is the C-terminal that provides specificity of interactions with other proteins. The subclass IV forms almost two third of the TRIM/RBCC family, possessing RFP- like B30.2 (PRY and SPRY) domains at C-terminal. While this ancient family has been reported to greatly diversify in vertebrates, in fish the B30.2 containing subclass appears prominent as well, with other human TRIMs having limited numbers of orthologues . Moreover, Meroni and Diez-Roux (2005) have reported almost 20 members of TRIM family also in invertebrates.
The TRIM E3 ubiquitin ligase family has emerged as a critical component in various cellular processes from cell development to apoptosis. For example, TRIM36 plays central role in arranging tlr4 during Xenopus embryogenesis ; TRIM59 and TRIM44 promotes proliferation in colorectal cancer and testicular germ tumor, respectively , ; TRIM24, TRIM28 and TRIM33 are well established transcriptional intermediary factors α, β and γ, respectively , , ; TRIM13, TRIM21, and Muscle Ring Fingers (MuRFs) are involved in autophagy , , , ; TRIM5α trimerizes to induce defense against HIV , whereas, TRIM21 negatively regulates IFN beta production after pathogen-recognition via degradation of IRF3 . Moreover, many TRIMs have been emerged as markers of carcinogenesis through their interaction with tumor protein p53 like TRIM24, TRIM28, TRIM29, and TRIM32 , , , . Interestingly, we found that TRIM is the major ‘single ring finger family’ that is known to be involved in cardiac pathophysiology including cardiomyocyte differentiation, signaling, apoptosis, cardiac hypertrophy/atrophy/ischemia, and dilated cardiomyopathy (Supplementary Table 1 and Supplementary Fig. 1).
Muscle Ring Fingers (MuRFs) comprising TRIM63 (MuRF1), TRIM55 (MuRF2) and TRIM54 (MuRF3) are the most studied TRIMs in the heart. However, with increasing knowledge of E3 ligases and recent advancements in the field, many other TRIMs such as TRIM8, TRIM21, TRIM24, TRIM32, TRIM45, TRIM69 and TRIM72 were found to play essential roles in cardiac function and disease pathways as discussed below and diagrammatically represented in Fig. 4.
MuRFs MuRF1, MuRF2, and MuRF3 have critical roles in skeletal and cardiac muscle. MuRF2 is found to be expressed at early onset of mouse cardiac differentiation, specifically at embryonic day 8.5 and thus is a sensitive marker for differentiating myocardium. In contrast, MuRF1 displays a strong upregulation postnatally, whereas, MuRF3 is expressed significantly only after birth . They characteristically lack B-box 1 and only have a COS domain at their carboxyl terminus. Nevertheless, MuRF1, 2, and 3 carries highly conserved RING domain at N-terminus and can form heterodimers by shared coiled-coil domains . Heterodimerization of MuRFs is possibly responsible for their multiple cellular localization and has been proposed to link titin filament and microtubule-dependent signal transduction pathways in striated muscles . Genetic mouse models of loss- or gain-of-function of MuRFs have provided deep insights into their cardiac roles. Cardiac-specific overexpression of MuRF1 led to thinning of left ventricular walls, worsened cardiac function, and heart failure upon TAC . MuRF1 has also been reported to regulate cardiac reactive oxygen species (ROS) production in mitochondria, revealing an additional cardio-protective role in ischemia reperfusion injury . Furthermore, MuRF1 inhibits cardiac fatty acid oxidation by specifically inhibiting its nuclear localization, suggesting a possible role in cardiac metabolism and pathophysiology . MuRF1 and MuRF2, two closely related family members, redundantly share functional similarities and can heterodimerize . Their functional similarity extends to a degree that presence of either MuRF1 or MuRF2 is sufficient for normal cardiac function and regulation of developmental physiological hypertrophy by modulating the expression and localization of E2F transcription factors . Simultaneous absence of both proteins however results in spontaneous development of skeletal and cardiac hypertrophy . MuRF2 labeled microtubules study in cardiac sarcomeres have demonstrated its vital contribution as a transient adaptor between microtubules, titin and nascent myosin filaments, thereby playing a significant role in signaling from sarcomere to nucleus . Also, rare variants of both MuRF1 & MuRF2 were found to be associated with human hypertrophic cardiomyopathy .