# TRIM proteins as emerging regulators of immune pathways: potential therapeutic targets in immune-related disorders **Authors:** Bilal Jawed, Rimsha Kanwal, Syed Khuram Zakir, Francesco Gaudio, Jessica Elisabetta Esposito, Azfar Athar Ishaqui, Stefano Martinotti, Matteo Botteghi, Elena Toniato PMC · DOI: 10.3389/fimmu.2026.1764253 · Frontiers in Immunology · 2026-02-11 ## TL;DR TRIM proteins regulate immune pathways and could be promising targets for treating immune-related disorders like autoimmune diseases. ## Contribution This review highlights the emerging therapeutic potential of TRIM proteins in immune-related disorders. ## Key findings - TRIM proteins modulate antiviral defense and cytokine production through immune signaling pathways. - Dysregulated TRIM activity is linked to autoimmune diseases such as SLE and rheumatoid arthritis. - Targeting TRIM proteins offers new clinical strategies for immune-related pathologies. ## Abstract Tripartite motif (TRIM) proteins constitute a versatile family of E3 ubiquitin ligases that regulate key signaling pathways governing innate and adaptive immune responses. Their ability to modify receptor-proximal adaptors, transcription factors, and pattern recognition receptors positions them as central modulators of antiviral defense, cytokine production, and immune homeostasis. Dysregulated TRIM expression or activity contributes to the pathogenesis of autoimmune diseases, including SLE, Sjögren’s syndrome, rheumatoid arthritis, psoriasis, inflammatory bowel diseases, and type I diabetes. This review summarizes the role of TRIM proteins in innate and adaptive immunity and their signaling axis linked to autoimmune and immune-related pathologies. It also focuses on the emerging therapeutic potential, targets and clinical strategies for targeting TRIM proteins. ## Linked entities - **Diseases:** SLE (MONDO:0007915), rheumatoid arthritis (MONDO:0008383), psoriasis (MONDO:0005083), type I diabetes (MONDO:0005147) ## Full-text entities - **Genes:** Ifnb1 (interferon beta 1, fibroblast) [NCBI Gene 15977] {aka IFN-beta, IFNB, If1da1, Ifb}, Zap70 (zeta-chain (TCR) associated protein kinase) [NCBI Gene 22637] {aka Srk, ZAP-70, mrtle, mur}, INSR (insulin receptor) [NCBI Gene 3643] {aka CD220, HHF5}, Pkm (pyruvate kinase, muscle) [NCBI Gene 18746] {aka Pk-2, Pk-3, Pk3, Pkm2}, IKBKG (inhibitor of nuclear factor kappa B kinase regulatory subunit gamma) [NCBI Gene 8517] {aka AMCBX1, EDAID1, FIP-3, FIP3, Fip3p, IKK-gamma}, Tlr3 (toll-like receptor 3) [NCBI Gene 142980], Irak4 (interleukin-1 receptor-associated kinase 4) [NCBI Gene 266632] {aka 8430405M07Rik, 9330209D03Rik, IRAK-4, NY-REN-64}, IL2 (interleukin 2) [NCBI Gene 3558] {aka IL-2, TCGF, lymphokine}, Nod2 (nucleotide-binding oligomerization domain containing 2) [NCBI Gene 257632] {aka ACUG, BLAU, CD, Card15, F830032C23Rik, IBD1}, Ticam2 (TIR domain containing adaptor molecule 2) [NCBI Gene 225471] {aka B430113A10, TICAM-2, TRAM, Tirp, Trif}, TRIM24 (tripartite motif containing 24) [NCBI Gene 8805] {aka PTC6, RNF82, TF1A, TIF1, TIF1A, TIF1ALPHA}, TRIM28 (tripartite motif containing 28) [NCBI Gene 10155] {aka KAP1, PPP1R157, RNF96, TF1B, TIF1B, TIF1beta}, UBE2L3 (ubiquitin conjugating enzyme E2 L3) [NCBI Gene 7332] {aka E2-F1, L-UBC, UBCH7, UbcM4}, Ifna (interferon alpha complex region) [NCBI Gene 111654] {aka Ifa, Ifa8}, TAB3 (TGF-beta activated kinase 1 (MAP3K7) binding protein 3) [NCBI Gene 257397] {aka MAP3K7IP3, NAP1}, Tlr7 (toll-like receptor 7) [NCBI Gene 170743], FOXP3 (forkhead box P3) [NCBI Gene 50943] {aka AIID, DIETER, IPEX, JM2, PIDX, XPID}, Traf6 (TNF receptor-associated factor 6) [NCBI Gene 22034] {aka 2310003F17Rik, C630032O20Rik}, CASP3 (caspase 3) [NCBI Gene 836] {aka CPP32, CPP32B, SCA-1}, PIK3CB (phosphatidylinositol-4,5-bisphosphate 3-kinase catalytic subunit beta) [NCBI Gene 5291] {aka P110BETA, PI3K, PI3KBETA, PIK3C1}, TRIM14 (tripartite motif containing 14) [NCBI Gene 9830], Ikbke (inhibitor of kappaB kinase epsilon) [NCBI Gene 56489] {aka IKK-E, IKK-i, IKKepsilon, Ikki}, Cgas (cyclic GMP-AMP synthase) [NCBI Gene 214763] {aka E330016A19Rik, Mb21d1}, Stat3 (signal transducer and activator of transcription 3) [NCBI Gene 20848] {aka 1110034C02Rik, Aprf}, Mavs (mitochondrial antiviral signaling protein) [NCBI Gene 228607] {aka D430028G21Rik, IPS-1, Visa, cardif}, NFKB1 (nuclear factor kappa B subunit 1) [NCBI Gene 4790] {aka CVID12, EBP-1, KBF1, NF-kB, NF-kB1, NF-kappa-B1}, Akt1 (Akt serine/threonine kinase 1) [NCBI Gene 11651] {aka Akt, LTR-akt, PKB, PKB/Akt, PKBalpha, Rac}, CD4 (CD4 molecule) [NCBI Gene 920] {aka CD4mut, IMD79, Leu-3, OKT4D, T4}, Trim31 (tripartite motif-containing 31) [NCBI Gene 224762] {aka HCG1, HCGI, RNF}, Trim3 (tripartite motif-containing 3) [NCBI Gene 55992] {aka BERP1, HAC1, Rnf22}, Nfkb2 (nuclear factor of kappa light polypeptide gene enhancer in B cells 2, p49/p100) [NCBI Gene 18034] {aka NF-kappaB2, lyt, p49, p49/p100, p50B, p52}, Il6 (interleukin 6) [NCBI Gene 16193] {aka Il-6}, IFNA1 (interferon alpha 1) [NCBI Gene 3439] {aka IFL, IFN, IFN-ALPHA, IFN-alphaD, IFNA13, IFNA@}, Ikbkg (inhibitor of kappaB kinase gamma) [NCBI Gene 16151] {aka 1110037D23Rik, IKK[g], NEMO}, IRF4 (interferon regulatory factor 4) [NCBI Gene 3662] {aka IMD131, LSIRF, MUM1, NF-EM5, SHEP8}, TRBV20OR9-2 (T cell receptor beta variable 20/OR9-2 (non-functional)) [NCBI Gene 6962] {aka CDR3, TCRBV20S2, TCRBV2O, TCRBV2S2O}, Il1 (interleukin 1 complex) [NCBI Gene 111343] {aka Il-1}, Mul1 (mitochondrial ubiquitin ligase activator of NFKB 1) [NCBI Gene 68350] {aka 0610009K11Rik, Gide, Tnrip-1}, TRIM5 (tripartite motif containing 5) [NCBI Gene 85363] {aka RNF88, TRIM5alpha}, TAB2 (TGF-beta activated kinase 1 (MAP3K7) binding protein 2) [NCBI Gene 23118] {aka CHTD2, MAP3K7IP2, TAB-2}, MAP3K7 (mitogen-activated protein kinase kinase kinase 7) [NCBI Gene 6885] {aka CSCF, FMD2, MEKK7, TAK1, TGF1a}, Nlrp6 (NLR family, pyrin domain containing 6) [NCBI Gene 101613] {aka Avr, Nalp6, Navr, Navr/Avr, Non-AVR, Pypaf5}, TRIM27 (tripartite motif containing 27) [NCBI Gene 5987] {aka RFP, RNF76}, Mal (myelin and lymphocyte protein, T cell differentiation protein) [NCBI Gene 17153] {aka Mpv17, Vip17}, Jak1 (Janus kinase 1) [NCBI Gene 16451] {aka BAP004, C130039L05Rik}, Trp53-ps (transformation related protein 53, pseudogene) [NCBI Gene 22060], Cxcl15 (C-X-C motif chemokine ligand 15) [NCBI Gene 20309] {aka Il8, Scyb15, lungkine, weche}, Map3k7 (mitogen-activated protein kinase kinase kinase 7) [NCBI Gene 26409] {aka B430101B05, Tak1}, Ifih1 (interferon induced with helicase C domain 1) [NCBI Gene 71586] {aka 9130009C22Rik, Helicard, Hlcd, MDA5, RLR-2}, Trim68 (tripartite motif-containing 68) [NCBI Gene 101700] {aka F730114J12Rik, Rnf137, SS-56}, IKBKB (inhibitor of nuclear factor kappa B kinase subunit beta) [NCBI Gene 3551] {aka IKK-2, IKK-beta, IKK2, IKKB, IMD15, IMD15A}, Bbox1 (gamma-butyrobetaine hydroxylase 1) [NCBI Gene 170442], Syk (spleen tyrosine kinase) [NCBI Gene 20963] {aka Sykb}, Irf3 (interferon regulatory factor 3) [NCBI Gene 54131] {aka C920001K05Rik, IRF-3}, Trim16 (tripartite motif-containing 16) [NCBI Gene 94092] {aka 9130006M08Rik, EBBP}, TRIM72 (tripartite motif containing 72) [NCBI Gene 493829] {aka MG53}, Klf9 (Kruppel-like transcription factor 9) [NCBI Gene 16601] {aka 2310051E17Rik, BTEB-1, Bteb1, Gm9971}, Myd88 (myeloid differentiation primary response gene 88) [NCBI Gene 17874], Tlr8 (toll-like receptor 8) [NCBI Gene 170744], IRS1 (insulin receptor substrate 1) [NCBI Gene 3667] {aka HIRS-1} - **Diseases:** T1D (MESH:D003922), autoimmune and immune-mediated disorders (MESH:C567355), serositis (MESH:D012700), Autoimmune (MESH:D001327), IBD (MESH:D015212), EAE (MESH:D004681), FMF (MESH:D010505), inflammatory cytokines (MESH:D000080424), neuronal damage (MESH:D009410), cartilage destruction (MESH:D002357), neurological impairment (MESH:D009422), UC (MESH:D003093), SLE (MESH:D008180), synovial hyperplasia (MESH:D006965), fever (MESH:D005334), atopic dermatitis (MESH:D003876), Psoriasis (MESH:D011565), TRIM dysregulation (MESH:D021081), -related (MESH:D019973), autoinflammatory condition (MESH:D056660), psoriatic (MESH:D015535), MS (MESH:D009103), viral infections (MESH:D014777), demyelination (MESH:D003711), RA (MESH:D001172), neurodegeneration (MESH:D019636), ET (MESH:D016751), bronchial inflammation (MESH:D007249), asthma (MESH:D001249), insulin resistance (MESH:D007333), neuroinflammation (MESH:D000090862), HSV-1 (MESH:D006561), cytotoxic (MESH:D064420), autoimmune and immune-related disorders (MESH:D007154), diabetes (MESH:D003920), cancer (MESH:D009369), SS (MESH:D012859), colitis (MESH:D003092), CD (MESH:D003424), infection (MESH:D007239) - **Chemicals:** STZ (MESH:D013311), LPS (MESH:D008070), iron (MESH:D007501), lipid (MESH:D008055), DSS (MESH:D016264), calcium (MESH:D002118), glucose (MESH:D005947), heparin (MESH:D006493), IMQ (MESH:D000077271), zinc (MESH:D015032), Ca2+ (-), MDP (MESH:D000119), cGAMP (MESH:C584311) - **Species:** Homo sapiens (human, species) [taxon 9606], Human endogenous retroviruses (clade) [taxon 206037], Mus musculus (house mouse, species) [taxon 10090] - **Cell lines:** Jurkat — Homo sapiens (Human), Childhood T acute lymphoblastic leukemia, Cancer cell line (CVCL_0065) ## Full text _Full body text omitted from this summary view._ Fetch the complete paper as Markdown: https://tomesphere.com/paper/PMC12934087/full.md ## Figures 4 figures with captions in the complete paper: https://tomesphere.com/paper/PMC12934087/full.md ## References 186 references — full list in the complete paper: https://tomesphere.com/paper/PMC12934087/full.md --- Source: https://tomesphere.com/paper/PMC12934087