MSRB1

MSRB1 is a selenocysteine-containing methionine-R-sulfoxide reductase that serves as the principal cytosolic and nuclear enzyme restoring oxidized methionine residues on proteins, thereby linking redox homeostasis to actin dynamics, innate and adaptive immunity, ion channel regulation, and synaptic plasticity. Its best-characterized function is the stereospecific reduction of Mical-oxidized Met44-R-sulfoxide on actin, which reverses actin disassembly and constitutes a conserved, reversible regulatory switch controlling actin polymerization in mammals and Drosophila (PMID:23911929, PMID:24212093). MsrB1 knockout mice exhibit elevated protein methionine sulfoxide and oxidative stress markers, GAPDH aggregation-driven inflammasome activation and sepsis susceptibility, impaired hippocampal LTP/LTD and spatial learning, and altered dendritic cell IL-12/STAT6 signaling that skews T-cell differentiation (PMID:18990697, PMID:36351405, PMID:31672630, PMID:33092166). MsrB1 also protects TRPM6 channel activity under oxidative stress by reducing Met1755 in the TRPM6 alpha-kinase domain (PMID:20584906).

1. 2007 Medium

   Establishing how MSRB1 transcription is controlled resolved a basic gene-regulation question: the promoter depends on three Sp1 sites and is silenced by DNA methylation, providing a mechanism for tissue- and context-specific expression.

   Evidence Promoter-reporter assays with mutant constructs, ChIP for Sp1, and 5-Aza-2'-deoxycytidine treatment in MDA-MB231 cells

   PMID:17519015

   Open questions at the time

   • No in vivo chromatin state data across tissues
   • Contribution of other transcription factors beyond Sp1 not addressed
2. 2008 High

   Generating the MsrB1 knockout mouse established that MsrB1 is the dominant cytosolic/nuclear MsrB enzyme in mammals and that its loss produces systemic oxidative stress, answering whether other MsrB family members compensate.

   Evidence MsrB1 KO mouse with biochemical assays for MsrB/MsrA activity, protein carbonyls, lipid peroxidation, glutathione status, and 75Se labeling across liver and kidney

   PMID:18990697

   Open questions at the time

   • Specific protein substrates responsible for the oxidative phenotype were not identified
   • A 5-kDa C-terminal fragment was detected but its function remains unknown
3. 2010 Medium

   Demonstrating that MsrB1 interacts with and functionally protects TRPM6 under oxidative stress identified the first specific protein substrate beyond general antioxidant defense, establishing a direct link between methionine sulfoxide reduction and ion channel regulation.

   Evidence Ras recruitment interaction screen, patch-clamp electrophysiology with co-expression, and site-directed mutagenesis of TRPM6 Met1755

   PMID:20584906

   Open questions at the time

   • Direct in vitro reduction of TRPM6 Met1755 by purified MsrB1 was not demonstrated
   • Physiological relevance in renal Mg²⁺ handling not tested in vivo
4. 2013 High

   Two independent studies showed that MsrB1/SelR stereospecifically reduces Mical-oxidized actin Met44-R-sulfoxide, establishing a conserved reversible oxidation/reduction switch that directly controls actin polymerization — a paradigm shift from viewing methionine oxidation solely as damage.

   Evidence In vitro actin reduction and polymerization assays (mammalian), genetic epistasis in Drosophila Semaphorin–Plexin signaling, and Met44 mutagenesis

   PMID:23911929 PMID:24212093

   Open questions at the time

   • Identity and roles of all actin methionine residues targeted in vivo remain incomplete
   • Whether MsrB1 is recruited to specific subcellular actin pools is unknown
5. 2019 Medium

   Linking MsrB1 loss to impaired hippocampal LTP/LTD and spatial memory revealed that its redox-repair activity is required for synaptic plasticity, extending its biological role to the nervous system.

   Evidence MsrB1 KO mice assessed by Morris water maze, hippocampal slice electrophysiology, and western blotting for synaptic proteins and CaMKII phosphorylation

   PMID:31672630

   Open questions at the time

   • Direct MsrB1 substrate in synapse not identified
   • Whether actin Met44 oxidation mediates the synaptic phenotype is untested
   • CaMKII Thr286 phosphorylation change is correlative
6. 2020 Medium

   Showing that MsrB1 regulates STAT6 phosphorylation in dendritic cells and IL-12-dependent Th1/Tfh differentiation established a role in adaptive immunity beyond its previously known innate immune functions.

   Evidence MsrB1 KO mice with DC activation assays, STAT6 western blot, IL-12 ELISA, T-cell differentiation, and immunization experiments

   PMID:33092166

   Open questions at the time

   • Whether MsrB1 directly reduces a methionine sulfoxide on STAT6 or an upstream regulator is unknown
   • In vivo immune challenge models beyond immunization not tested
7. 2022 Medium

   Identifying GAPDH Met44 as a specific MsrB1 substrate in macrophages linked methionine sulfoxide accumulation to GAPDH aggregation, inflammasome activation, and sepsis susceptibility, providing a molecular mechanism for MsrB1's anti-inflammatory role.

   Evidence MsrB1 KO mice, LPS-induced sepsis, GAPDH aggregation assay, inflammasome and IL-1β measurements

   PMID:36351405

   Open questions at the time

   • Direct in vitro enzymatic reduction of GAPDH Met44 by MsrB1 was not reconstituted
   • Contribution of other Met residues on GAPDH not assessed
8. 2024 Medium

   Development of active-site inhibitors validated by a biosensor screen and in vivo ear edema model provided the first pharmacological tools for MsrB1 and confirmed that catalytic activity underlies its anti-inflammatory cytokine regulation.

   Evidence Fluorescence biosensor (RIYsense) high-throughput screen, molecular docking, enzymatic inhibition assays, and mouse ear edema model

   PMID:39594490

   Open questions at the time

   • Inhibitor selectivity over MsrB2/MsrB3 not reported
   • Pharmacokinetic and off-target profiles not characterized

• Major open questions include the full substrate repertoire of MsrB1 in different tissues, how MsrB1 is recruited to specific substrates (actin pools, GAPDH, STAT6 pathway components), the function of the 5-kDa C-terminal fragment, and whether MsrB1 catalytic activity can be therapeutically targeted in inflammatory or neurodegenerative disease.
• Comprehensive substrate identification (e.g., by substrate trapping or proteomics) has not been performed
• Structural basis for substrate recognition beyond actin is lacking
• Function of the 5-kDa MsrB1 fragment is uncharacterized