The Tripartite Motif Containing 25, or TRIM25, protein is a versatile player found within human cells. It participates in numerous fundamental biological processes, acting as a sophisticated regulator. Its involvement spans from defending against invading pathogens to influencing how our cells grow and respond to various internal and external signals. Understanding TRIM25 provides insight into the complex mechanisms that govern cellular function and overall well-being.
Understanding TRIM25
TRIM25 belongs to the tripartite motif (TRIM) protein family, characterized by a conserved structural arrangement. It functions as an E3 ubiquitin ligase, an enzyme that attaches small protein tags called ubiquitin to other proteins. Ubiquitination acts like a cellular tag, marking proteins for degradation, altering their activity, or directing them to specific locations within the cell.
The structure of TRIM25 includes several distinct domains: an N-terminal RING domain, two B-box domains (type 1 and type 2), a coiled-coil domain (CCD), and a C-terminal SPRY domain. The RING domain is responsible for recruiting ubiquitin-conjugating enzymes. The CCD domain is involved in forming multimers, while the SPRY domain helps TRIM25 recognize and bind to its target proteins. TRIM25 is primarily located in the cytoplasm of cells, though it can also be found in the nucleoplasm and stress granules.
TRIM25’s Role in Antiviral Defense
TRIM25 plays a prominent role in the body’s innate immune system, serving as a first line of defense against viral infections. Its most well-documented function involves activating the RIG-I (retinoic acid-inducible gene I) signaling pathway, a crucial component that senses viral RNA in the cytoplasm. Upon detecting viral RNA, RIG-I undergoes a conformational change, and TRIM25 then attaches ubiquitin chains to RIG-I, specifically K63-linked polyubiquitination. This ubiquitination acts as a signal, promoting the assembly of signaling complexes that lead to the production of type I interferons, powerful antiviral proteins that restrict viral replication.
TRIM25’s antiviral actions extend to specific viruses, including influenza A viruses (IAV) and coronaviruses like SARS-CoV-2. For influenza, TRIM25 targets the viral non-structural protein 1 (NS1), which is a known viral immune evasion protein. NS1 can interfere with TRIM25’s ability to ubiquitinate RIG-I, thereby suppressing the antiviral response. Beyond RIG-I activation, TRIM25 can also destabilize IAV messenger RNAs (mRNAs), reducing viral protein synthesis, and has a nuclear role in inhibiting viral RNA synthesis by targeting viral ribonucleoproteins.
SARS-CoV-2 infection can upregulate TRIM25 expression, leading to increased activation of RIG-I and another antiviral protein called ZAP (zinc-finger antiviral protein) through ubiquitination, which in turn boosts interferon production. However, some coronaviruses, such as SARS-CoV and MERS-CoV, have evolved strategies to counteract TRIM25’s activity. Their nucleocapsid proteins can bind to TRIM25’s SPRY domain, hindering its ability to activate RIG-I and promoting viral invasion.
Diverse Roles of TRIM25 in Cellular Processes
Beyond its antiviral functions, TRIM25 participates in a variety of other fundamental cellular activities. It directly and indirectly regulates processes such as cell growth, proliferation, and differentiation. This influence often stems from its E3 ligase activity, where it modifies target proteins through ubiquitination, affecting their stability or signaling capabilities. For instance, TRIM25 can modify proteins via K63- or K48-linked polyubiquitination, which can either activate signaling pathways or lead to protein degradation, respectively.
TRIM25 also plays a part in inflammation pathways and cellular responses to stress. It modulates the levels and activity of p53, a tumor suppressor protein, and influences the nuclear localization of Nrf2, a protein involved in antioxidant defenses. Furthermore, TRIM25 has been identified as an RNA-binding protein, with its ability to bind to various RNAs potentially influencing its ubiquitination activity, subcellular localization, and overall cellular functions.
Implications of TRIM25 Dysfunction
When TRIM25 does not function properly, through overactivity, underactivity, or mutations, it can contribute to various diseases. Its dysregulation has been linked to several types of cancer. For example, in breast and endometrial cancers, TRIM25 can promote cancer cell survival and proliferation by degrading protein 14-3-3σ, which destabilizes p53 and attenuates its tumor-suppressive signaling. In hepatocellular carcinoma, TRIM25 can target Keap1 for degradation, activating the Nrf2 pathway and enhancing antioxidant defenses that promote cancer cell survival.
TRIM25 dysfunction is also implicated in neurodegenerative disorders. A nonsense mutation (p.C168) in the TRIM25 gene has been identified as a cause of early-onset autosomal dominant dementia, accompanied by amyloid plaque accumulation and parkinsonism. This highlights the broader impact of E3 ubiquitin ligase dysregulation in neurodegeneration. TRIM25 is also linked to inflammation, with its inhibition potentially attenuating inflammation, senescence, and oxidative stress in microvascular endothelial cells. These connections underscore the influence of TRIM25 on cellular homeostasis and its potential as a target for therapeutic interventions in various pathological conditions.