TIF-1

TIF1 is a protein that belongs to the TRIM superfamily (TRIM = tripartite motif) and occurs in four subtypes known as TIF1-α (TRIM24), TIF1-β (TRIM28), TIF1-γ (TRIM33 -s.a. TRIM33 gene) and TIF1-δ (TRIM66). All subtypes have similar structures, which include an N-terminal TRIM that is a protein-protein and oligomerization interface and contains a ring-B-box-coiled-coil (RBCC) domain, a central TIF1 signature sequence (TSS) domain and a C-terminal combination of plant homeodomain (PHD) and bromodomain.

Since TRIM is a ubiquitin ligase involved in protein modification and the C-terminal chromatin binding unit performs epigenetic transcriptional regulation, TIF1 may have multifunctional protein properties.

TIF1γ is thought to play a role in transcription elongation, DNA repair, cell differentiation, embryonic development and mitosis (Hatakeyama S 2011; Yu C et al. 2019; Venturini L et al. 1999). TIF1γ is a 123 kDa protein that consists of 1120 amino acids and is encoded by the TRIM33 gene. At the N-terminus is an RBCC unit containing a RING domain, B-boxes and a coiled-coil domain, all of which are involved in the ubiquitination of Smad4. At the C-terminus is a PHD bromodomain that can interact with histones 3 and 4, while a middle linker region that interacts with activated Smad2 and Smad3 connects the two termini (Yu C et al. 2019).

The transforming growth factor-β (TGF-β) signaling pathway plays an important role in cancer initiation and development as it can regulate cell proliferation, differentiation, apoptosis, motility, invasion and immune responses. TIF1γ is involved in the regulation of the TGF-β signaling pathway (Massague J 2008; Wang L et al. 2016). TIF1γ regulates the TGF-β/Smad signaling pathway via monoubiquitinated Smad4 and/or acts as a cofactor for the p-Smad2/3 complex, competes with Smad4 and thus inhibits the formation of the Smad2/3/4 complex. Furthermore, TIF1γ has been shown to inhibit tumor growth, TGF-β-induced EMT and metastasis (Yu C et al. 2019). In various malignant tumors, such as non-small cell lung cancer, breast cancer, glioma and clear cell renal cell carcinoma, TIF1γ acts as a tumor suppressor and shows reduced expression. In glioblastoma, TIF1γ can regulate the Wnt/β-catenin signaling pathway by degrading β-catenin through ubiquitination, leading to inhibition of cell proliferation and tumorigenesis. Overall, TIF1γ suppresses tumors via the TGF-β/Smad and Wnt/β-catenin signaling pathways in various cancer types (Kotobuki Y et al. 2020)

Anti-TIF1γ antibody-positive dermatomyositis: Anti-TIF1 antibodies are described as anti-155/140 and anti-p155 antibodies targeting a 155 kDa nuclear protein with or without a 140 kDa protein (Kotobuki Y et al. 2020). The 155 kDa nuclear protein and the 140 kDa protein were subsequently identified as TIF1γ and TIF1α, respectively. Anti-TIF1 antibodies are detected in both JDM and adult-onset DM.

In DM with anti-TIF1 antibodies, myositis is usually mild. Anti-TIF1γ antibodies are found in 7-31% of adult DM patients and are positively associated with malignant tumors and dysphagia, but negatively associated with interstitial lung disease (ILD), Raynaud's phenomenon and arthritis/arthralgia (Kotobuki Y et al. 2020). In contrast, none of the anti-TIF1γ antibody-positive DM patients under 40 years of age (including JDM) had malignant tumors. In addition, a recent study suggests that pregnancy may be one of the triggers for the occurrence of anti-TIF1γ antibody-positive DM in young adult female patients (Kotobuki Y et al. 2020).

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