TXNL1

TXNL1 (TRP32) is a cytoplasmic thioredoxin-fold protein that couples redox chemistry to protein quality control by serving as a redox-active cofactor of the 26S proteasome (PMID:19349277, PMID:40770113). Its N-terminal thioredoxin domain carries a conserved active site and reduces interchain disulfides in vitro, functioning in a TrxR1 (TXNRD1)-coupled cycle to reduce insulin, cystine, and GSSG, while a distinct ATP-independent chaperone activity that prevents protein aggregation operates independently of the redox-active cysteines (PMID:9668102, PMID:37804695). TXNL1 docks onto the 19S regulatory particle through contacts with Rpn2/PSMD1, Rpn10/PSMD4, and Rpn11/PSMD14, with its PITH domain anchored above the Rpn11 deubiquitinase; binding is conformation-dependent, and in the actively degrading proteasome the C-terminal tail covers Rpn11's catalytic groove and coordinates its active-site Zn2+, positioning TXNL1 to reduce substrates prior to proteolysis and to modulate Rpn11 activity [PMID:40770113, PMID:41198955, PMID:bio_10.1101_2025.07.31.667872]. The protein engages substrate-handling and target factors of this system, forming a disulfide-linked intermediate with eEF1A1 and driving downregulation of XRCC1 through the ubiquitin-proteasome pathway, and its C-terminal domain selectively reduces oxidized PRL phosphatases (PMID:19349277, PMID:23362275, PMID:24525731). TXNL1 is itself a proteasome substrate, undergoing ubiquitin-independent degradation upon exposure to metal/metalloid oxidative agents, with arsenic repressing TXNL1 via a DNMT1-USP10 axis that increases its ubiquitination and proteasomal turnover (PMID:40770113, PMID:41275040). Beyond these roles, TXNL1 has been linked to fluid-phase endocytosis through GDI-mediated Rab5 capture and to cisplatin-induced apoptosis in gastric cancer cells (PMID:17987124, PMID:25348020).

1. 1998 High

   Established TXNL1/TRP32 as a bona fide thioredoxin-family reductase, defining its core biochemical activity before any cellular role was known.

   Evidence Co-purification from thymoma cells, molecular cloning, and in vitro insulin disulfide reduction with cytoplasmic localization by fractionation/immunostaining

   PMID:9668102

   Open questions at the time

   • No physiological substrate identified
   • Significance of co-purification with MST kinase fragment not resolved
   • Reason for greater oxidation sensitivity than Trx1 unexplained
2. 2007 Medium

   Linked TXNL1 redox activity to a cellular trafficking output, proposing it as a redox sensor for fluid-phase endocytosis.

   Evidence Biochemical co-purification of a p38MAPK-containing complex with Rab5 capture and endocytosis assays

   PMID:17987124

   Open questions at the time

   • GDI/Rab5 redox link proposed but not reconstituted
   • Direct substrate of TXNL1 in this pathway unknown
   • Composition of the p38MAPK complex not fully defined
3. 2009 High

   Identified TXNL1 as a redox cofactor physically bound to the proteasome 19S particle and nominated eEF1A1 as a substrate, connecting its thioredoxin chemistry to protein degradation.

   Evidence Co-purification with 26S proteasome, Cys-to-Ser trapping mutant forming a disulfide with eEF1A1, redox potential measurement, and siRNA knockdown stabilizing ubiquitin conjugates

   PMID:19349277

   Open questions at the time

   • Functional consequence of eEF1A1 reduction not established
   • Only moderate ubiquitin-conjugate stabilization on knockdown
   • Binding interface on the proteasome not mapped structurally
4. 2013 High

   Defined a substrate-specific reductase function, showing TXNL1's unique C-terminal domain selectively reduces oxidized PRL phosphatases.

   Evidence In vitro reduction assays comparing Trx-related proteins, truncation mapping of the PRL-interacting domain, and knockdown prolonging H2O2-induced PRL oxidation

   PMID:23362275

   Open questions at the time

   • Downstream signaling consequence of PRL reduction not addressed
   • Whether PRL reduction requires proteasome binding unknown
5. 2014 Medium

   Connected TXNL1's proteasome-cofactor role to a disease-relevant target, the BER protein XRCC1, in chemoresistance.

   Evidence Proteomics, Western blotting, and cisplatin resistance assays in sensitive vs. resistant gastric cancer lines

   PMID:24525731

   Open questions at the time

   • Direct vs. indirect control of XRCC1 turnover not resolved
   • Ubiquitin-proteasome step inferred, not reconstituted
6. 2015 Medium

   Placed TXNL1 upstream of mitochondrial apoptosis, showing it sensitizes gastric cancer cells to cisplatin.

   Evidence siRNA knockdown and overexpression with TUNEL, clonogenic assays, and Bcl-2 pathway Western blotting

   PMID:25348020

   Open questions at the time

   • Molecular mechanism linking TXNL1 to Bcl-2 not defined
   • Pathway placement based on expression changes only
7. 2018 Medium

   Implicated TXNL1 in antiviral apoptotic signaling through interaction with Newcastle disease virus V protein.

   Evidence Yeast two-hybrid, co-localization, and overexpression/knockdown with apoptosis and replication readouts in DF-1 cells

   PMID:30290847

   Open questions at the time

   • Interaction not validated by reciprocal biochemical methods
   • Mechanism by which V protein modulates TXNL1 unclear
8. 2023 High

   Resolved TXNL1 as a dual-function protein, separating its TrxR1-coupled reductase activity from a cysteine-independent chaperone activity.

   Evidence Recombinant reconstitution, Cys-to-Ser mutagenesis, disulfide reduction and chaperone aggregation assays, and Km determination

   PMID:37804695

   Open questions at the time

   • High Km for TrxR1 raises question of physiological reductant
   • Substrate specificity of chaperone activity not defined
9. 2025 High

   Provided the structural basis for proteasome engagement, mapping TXNL1 contacts to PSMD1, PSMD4, and PSMD14 and showing proteasome binding is required for its stress-induced ubiquitin-independent degradation.

   Evidence Cryo-EM structure of TXNL1 on the 19S particle plus oxidative-stress degradation assays with metal/metalloid agents

   PMID:40770113

   Open questions at the time

   • Trigger converting binding into degradation not defined
   • Identity of substrates reduced at this site unconfirmed
10. 2025 High

    Demonstrated conformation-dependent binding tied to the proteasome ATPase motor state, with the TXNL1 C-terminal tail capping Rpn11 and coordinating its Zn2+ during active degradation.

    Evidence Time-resolved cryo-EM at varying TXNL1 concentrations with biophysical and biochemical binding assays

    PMID:41198955

    Open questions at the time

    • Net effect on Rpn11 deubiquitinase output during degradation not quantified
    • Coupling between substrate reduction and degradation timing unclear
11. 2025 Medium

    Defined a regulatory circuit controlling TXNL1 abundance, in which arsenic represses USP10 via DNMT1-driven promoter methylation to promote TXNL1 ubiquitination and turnover.

    Evidence Knockdown/overexpression, promoter methylation and ubiquitination assays, and ROS/DNA damage/transformation readouts in vitro and in vivo

    PMID:41275040

    Open questions at the time

    • Direct USP10-TXNL1 deubiquitination not biochemically reconstituted
    • Relationship to ubiquitin-independent degradation pathway unresolved

• How TXNL1's redox/chaperone activities are functionally coupled to substrate reduction at the proteasome catalytic site, and which endogenous substrates this serves, remains open.
• No comprehensive census of proteasome substrates reduced by TXNL1
• Physiological reductant given high TrxR1 Km undetermined
• In vivo consequence of modulating Rpn11 during degradation not established