TRIM48

TRIM48 is a RING-domain E3 ubiquitin ligase that regulates oxidative stress signaling, innate antiviral immunity, and cell proliferation through ubiquitin-dependent substrate targeting. TRIM48 promotes K48-linked polyubiquitination and proteasomal degradation of PRMT1, thereby relieving PRMT1-mediated inhibition of ASK1 and facilitating oxidative stress-induced ASK1 activation and cell death (PMID:29186683); this TRIM48–PRMT1 interaction is competitively disrupted by TK1 and KTN1, which stabilize PRMT1 in hepatocellular and gastric carcinoma contexts (PMID:37071992, PMID:37554218). TRIM48 also functions as a ubiquitin ligase activity-dependent negative feedback regulator of RIG-I signaling, suppressing IRF3 and NF-κB nuclear translocation, IFN-β expression, and antiviral responses (PMID:40609779). TRIM48 itself is a short-lived protein targeted for K48-linked polyubiquitination and proteasomal degradation by the SCF-FBXO22 complex, establishing a regulatory circuit in which FBXO22 controls TRIM48 abundance and thereby modulates ASK1 activation (PMID:41096745).

1. 2017 High

   Identification of TRIM48 as an E3 ligase for PRMT1 established its first known substrate and linked it to oxidative stress-induced ASK1 activation and cell death, answering what molecular activity TRIM48 performs and what signaling pathway it controls.

   Evidence Pull-down screen, K48-linked ubiquitination assays, TRIM48 knockdown/overexpression with ASK1 activation readouts, and mouse xenograft model

   PMID:29186683

   Open questions at the time

   • Direct ubiquitination site(s) on PRMT1 not mapped
   • Structural basis of TRIM48–PRMT1 recognition unknown
   • Mechanism of TRIM48 regulation (transcriptional or post-translational) not addressed
2. 2019 Medium

   Demonstration that TRIM48 suppresses ERK1/2 signaling and arrests glioblastoma cell cycle progression revealed a second pathway regulated by TRIM48, though the direct molecular target upstream of ERK1/2 remained undefined.

   Evidence Lentiviral overexpression and siRNA knockdown in GBM cell lines with pharmacological ERK1/2 pathway rescue (curcumin, PD98059), proliferation and cell cycle assays

   PMID:31703057

   Open questions at the time

   • Direct substrate linking TRIM48 to ERK1/2 suppression not identified
   • Whether TRIM48's E3 ligase activity is required for ERK1/2 regulation not tested
   • Findings limited to glioblastoma cell lines
3. 2023 Medium

   Discovery that TK1 and KTN1 each competitively disrupt the TRIM48–PRMT1 interaction to stabilize PRMT1 revealed that the TRIM48-PRMT1 axis is subject to upstream modulation, explaining how PRMT1 escapes degradation in specific cancer contexts.

   Evidence Co-IP and ubiquitination assays in hepatocellular carcinoma (TK1) and gastric cancer (KTN1) cell lines showing competitive displacement of TRIM48 from PRMT1

   PMID:37071992 PMID:37554218

   Open questions at the time

   • Whether TK1 and KTN1 bind the same or overlapping sites on PRMT1 is unknown
   • Competitive inhibition demonstrated by Co-IP; direct binding domains not mapped
   • In vivo relevance of competitive disruption not tested
4. 2025 High

   Identification of SCF-FBXO22 as the E3 ligase that targets TRIM48 itself for K48-linked ubiquitination and proteasomal degradation closed the regulatory loop, showing TRIM48 is a short-lived protein whose abundance gates ASK1 activation.

   Evidence Cycloheximide chase, siRNA knockdown of Skp1/Cul1/FBXO22 stabilizing TRIM48, exogenous FBXO22 promoting TRIM48 ubiquitination, epistasis with TRIM48 KD reversing FBXO22-KD phenotype on ASK1

   PMID:41096745

   Open questions at the time

   • FBXO22 recognition motif (degron) on TRIM48 not mapped
   • Whether FBXO22-mediated TRIM48 turnover is regulated by oxidative stress signals not determined
   • Impact on RIG-I or ERK1/2 pathways not tested
5. 2025 High

   An unbiased genome-wide screen established TRIM48 as a ligase activity-dependent negative feedback regulator of RIG-I–mediated innate immune signaling, expanding its functional repertoire beyond PRMT1/ASK1 to antiviral defense.

   Evidence Genome-wide siRNA screen of 616 E3 ligases, live-cell IRF3/NF-κB translocation imaging, Rift Valley Fever reporter virus, IFN-β reporter and mRNA assays, catalytic-dead mutant

   PMID:40609779

   Open questions at the time

   • Direct substrate in the RIG-I pathway not identified
   • Whether TRIM48 ubiquitinates RIG-I itself or a downstream component is unknown
   • Physiological relevance during viral infection in vivo not demonstrated

• Key open questions include the identity of TRIM48's direct substrate in RIG-I and ERK1/2 signaling, structural basis of substrate recognition, whether TRIM48 turnover by SCF-FBXO22 is signal-regulated, and integration of its roles across oxidative stress, innate immunity, and proliferation pathways.
• No structural data for TRIM48 or any of its substrate complexes
• RIG-I pathway substrate not identified
• ERK1/2 pathway substrate not identified
• Signal-dependent regulation of TRIM48 stability not characterized