TRIM33 gene

TRIM33 (TRIM33 stands for: Tripartite Motif Containing 33) is a human protein-coding gene located on chromosome 1p13.2. The encoded protein belongs to the TRIM superfamily (TRIM = Tripartite motif) and occurs in four subtypes known as:

• TIF1-α (TRIM24)
• TIF1-β (TRIM28)
• TIF1-γ (TRIM33) and
• TIF1-δ (TRIM66)

are known. 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 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.) Thus, the protein TIF1-γ encoded by this gene is considered a transcriptional corepressor. An important paralog of this gene is TRIM66.

The protein encoded by this gene, transcriptional intermediary factor 1 gamma (TIF-1), is considered a transcriptional co-repressor. However, molecules that interact with this protein have not yet been identified. The protein belongs to the family of proteins with a tripartite motif. This motif comprises three zinc-binding domains, a RING, a B-box type 1 and a B-box type 2 as well as a coiled-coil region.

TIF1-γ has been shown to play a role in transcription elongation, DNA repair, cell differentiation, embryonic development and mitosis. 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.

The signaling pathways associated with the encoded protein include gene expression (transcription) and transcriptional activity of the SMAD2/SMAD3:SMAD4 heterotrimer (see Smad proteins below).

The encoded protein TIF1-γ:

• acts as an E3 ubiquitin-protein ligase
• promotes SMAD4 ubiquitination
• promotes exclusion from the nucleus and degradation via the ubiquitin-proteasome pathway.
• plays a role in the control of cell proliferation.

Its association with SMAD2 and SMAD3 stimulates erythroid differentiation of hematopoietic stem/progenitor cells (By similarity). Monoubiquitinates SMAD4 and acts as an inhibitor of the SMAD4-dependent TGF-beta/BMP signaling cascade (monoubiquitination of SMAD4 hinders its ability to form a stable complex with activated SMAD2/3, leading to inhibition of the TGF-beta/BMP signaling cascade).

Diseases associated with TRIM33 include differentiated thyroid carcinoma and orbital plasma cell granuloma.

Antibodies against the TIF1-gamma protein are specific antibodies that occur in paraneoplastic dermatomyositis.

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3. Volc-Platzer B (2015) Dermatomyositis update. Dermatology 66:604-610

4. Wang WY et al (2024) Anti-TIF-a-gamma associated dermatomyositis in recurrent triple-negative breast cancer. JDDG 20: 1008-1012

5. Wang L et al. (2016) Repression of TIF1γ by SOX2 promotes TGF-β-induced epithelial-mesenchymal transition in non-small-cell lung cancer. Oncogene 35:867-877.
6. Yu C et al. (2019) The roles of TIF1γ in cancer. Front Oncol 9:979