This gene was identified as an estrogen and anti-estrogen regulated gene in epithelial cells stably expressing estrogen receptor. The protein encoded by this gene contains two B box domains and a coiled-coiled region that are characteristic of the B box zinc finger protein family.
The proteins of this family have been reported to be involved in a variety of biological processes including cell growth, differentiation and pathogenesis. Expression of this gene was detected in most tissues. Its function, however, has not yet been determined.[5]
Tripartite motif-containing protein 16, also known as TRIM16, is a protein encoded by the TRIM16 gene in humans. It is part of the TRIM family of proteins, characterized by one or two B-box domains and a coiled-coil region. Recent research showed that TRIM16 acts as an E3 ubiquitin ligase and molecular scaffold that participates in protein-quality control, tumor suppression, and protection against cardiac hypertrophy.[6][7][8] TRIM16 is expressed in many tissues and participates in cellular pathways that maintain proteostasis and regulate stress responses.[9]
Structure
The protein contains two B-box domains and a coiled-coil motif typical of the TRIM family, but lacks a canonical RING domain. These structural elements allow TRIM16 to mediate protein-protein interactions and to act as a ubiquitin-ligase adaptor. Early studies identified it as an estrogen-responsive gene in epithelial cells expressing the estrogen receptor, and expression has since been observed in most human tissues.[9]
Despite the absence of a RING domain, TRIM16 executes many of the activities normally associated with TRIM proteins. It was called by researchers a "RING-less TRIM," with much of the functional responsibility taken over by a B-box domain. These domains are considered important for stress response signaling because of their zinc binding, interactions with other TRIM members, and assembly into multiprotein complexes (Raymond et al., 2001). Because of its coiled-coil region, TRIM16 is able to form dimers or larger oligomers and thus act as a scaffold for several interacting partners at once. Its structural flexibility probably accounts for TRIM16's participation in such a wide range of cellular processes.
The original identification of TRIM16, formerly known as EBBP, as an estrogen-regulated gene suggested that its expression[9] might be influenced by hormonal signals. Soon enough, investigators were able to determine that TRIM16 is highly expressed throughout a variety of tissues, such as heart, liver, lung, and skin.[9] Such broad expression provides further support for the hypothesis that TRIM16 functions as a stress-response protein with widespread actions rather than being specialized to specific cell types. Its presence in both the cytoplasm and nucleus further indicates that TRIM16 plays roles in multiple cellular compartments.
TRIM16s evolutionary position within the TRIM family provides a further insight into its possible functions beyond the structural domains themselves. TRIM16 shares many of the characteristics of the TRIM family, which has become well-known for its role in immunity, antiviral defense, and stress responses (Reymond et al., 2001). A number of studies suggest that TRIM16's B-box domains partially compensate for the absence of the RING domain, usually associated with E3 ubiquitin ligase activity, either by recruiting other E3 ligases to form functional complexes or by providing limited ligase function. This makes TRIM16 unusual but not inactive in ubiquitination processes.
Function
TRIM16 has indeed been found to modulate both the formation and turnover of misfolded protein aggregates. Carroll et al., 2018, report that TRIM16 functions as an E3 ubiquitin ligase that bridges ubiquitinated substrates to autophagic receptors, integrating the sequestration of aggregation-prone proteins and stimulating their autophagic degradation.[6] In light of its two roles in the formation and removal of aggregates, TRIM16 may play a role in maintaining protein homeostasis under cellular stress.
Further investigation revealed that TRIM16 is intimately associated with the p62-KEAP1-NRF2 pathway, a significant oxidative stress regulator. Usually, KEAP1 binds NRF2 and targets it for degradation, but under oxidative stress, TRIM16 disrupts this interaction and stabilizes NRF2, leading to the increased expression of antioxidant genes.[6] TRIM16 thus serves as a link between the antioxidant response and the protein-quality control system.
TRIM16 also acts as a platform for other autophagy-related proteins, including ULK1, ATG16L1, and LC3B, thereby facilitating the formation of autophagosomes responsible for the degradation of damaged proteins.[6]In this regard, TRIM16 helps cells cope with a proteotoxic environment by orchestrating protein aggregate formation and subsequent disassembly. Because TRIM16 can promote aggregate formation when conditions require it and then favor its subsequent degradation, this makes TRIM16 an exceptionally versatile component of the proteostasis network.
TRIM16 also interacts with transcription factor E2F1 and cytoskeletal protein vimentin, thus modulating cell-cycle progression and structural stability, and further extends its reach outside of stress regulation into the realm of general cell behavior.[7]
Clinical significance
Tumor suppression
Moreover, TRIM16 safeguards the cardiovascular system. In neuroblastoma and other cancer models, TRIM16 can take on a tumor suppressive function. Marshall et al. 2010 demonstrated how TRIM16 suppresses cell migration and proliferation by interacting with the cytoskeletal protein vimentin and the transcription factor E2F1.[7]Such interactions reduce tumor growth and oncogenic signaling, thus providing evidence that loss in the activity of TRIM16 may facilitate cancer development.
Further study has identified that many aggressive cancers have reduced expression of TRIM16, which impairs the cell's ability to regulate cell proliferation and maintain structural integrity.[7] The tumor suppressor capabilities of TRIM16 were also supported by studies where forced expression of TRIM16 in tumor cells diminished growth and metastatic potential. TRIM16 also was associated with the retinoic acid signaling pathway, a differentiation pathway that can push cancer cells toward less malignant states.[9]
Cardiac hypertrophy
TRIM16 also has a protective function in the cardiovascular system. As Liu et al. (2021) established, TRIM16 restricts oxidative stress and cardiomyocyte hypertrophy by repressing pathological cardiac hypertrophy through the PRDX1-Nrf2 antioxidant pathway.[8] This finding broadens the physiological importance of TRIM16 from cell biology to whole-organ protection against stressful conditions.
The study in Circulation Research further showed that TRIM16 controls the activity of SRC kinase by labeling it for K48-linked ubiquintation, thereby decreasing SRC's contribution to hypertrophic signaling.[8] It further modulates the activity of PRDX1 to promote NRF2-HO-1 pathway activation and increase antioxidant capacity in cardiomyocytes.[8] This set of interactions protects the heart from oxidative damage and abnormal structural enlargement.
Overexpression of TRIM16 in mouse models prevented the development of more severe hypertrophy, increased fibrosis, and decreased heart function caused by TRIM16 loss. In addition, reduced TRIM16 levels were found in human hypertrophic heart samples, suggesting a potential diagnostic or therapeutic role. Integrative Significance Combined, the findings of the studies reported in the EMBO Journal [6]and Circulation Research[8] show that TRIM16 is at the interface of antioxidant control and proteostasis through cell cycle regulation to structural integrity. TRIM16 plays the role of a major coordinator of cellular stress responses with connectivity to key pathways such as p62-NRF2 and PRDX1-SRC-NRF2. Its role in different tissues and disease conditions is emphasized by dual functions that include the regulation of misfolded protein aggregates and the protection of the heart from pathological remodeling. TRIM16 acts to stabilize NRF2 pathways by maintaining a robust cellular stress-response machinery that is essential for maintaining health at both the cellular and organ levels. Such an integrated knowledge places TRIM16 as a putative drug target for diseases related to oxidative stress, protein misfolding, or hypertrophic remodeling.
12345Liu J, Li W, Deng KQ, Tian S, Liu H, Shi H, etal. (May 2022). "The E3 Ligase TRIM16 Is a Key Suppressor of Pathological Cardiac Hypertrophy". Circulation Research. 130 (10): 1586–1600. doi:10.1161/CIRCRESAHA.121.318866. PMID35437018.
Munding C, Keller M, Niklaus G, Papin S, Tschopp J, Werner S, etal. (November 2006). "The estrogen-responsive B box protein: a novel enhancer of interleukin-1beta secretion". Cell Death and Differentiation. 13 (11): 1938–1949. doi:10.1038/sj.cdd.4401896. PMID16575408. S2CID8953820.
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