Msra-KO Mouse

MsrA, short for methionine sulfoxide reductase A, is an enzyme that can reduce oxidized methionine residues. Methionine, a sulfur-containing amino acid, can act as a functional redox switch, and MsrA rescues it from the reversible oxidation of methionine sulfoxide. This function is crucial for maintaining protein function and protecting cells from oxidative stress. It is involved in multiple biological pathways such as redox biology and is of great biological importance in various organisms from bacteria to mammals [1,2,3,5].

In pancreatic ductal adenocarcinoma (PDA), MsrA acts as a suppressor of metastasis. Loss of MsrA in primary PDA cells promotes migration and invasion, likely through the selective oxidation of a methionine residue (M239) in pyruvate kinase M2 (PKM2), which sustains PKM2 in an active tetrameric state to promote respiration, migration, and metastasis [1]. In atrial fibrillation, S-Methyl-L-cysteine (SMLC) can target MsrA to attenuate angiotensin II (Ang II)-induced oxidative stress and atrial remodeling via the p38 MAPK signaling pathway. Knockdown of MsrA could attenuate the protective effects of SMLC [2]. In demyelination, MsrA suppresses the inflammatory activation of microglia and oxidative stress to prevent demyelination via inhibition of the NOX2-MAPKs/NF-κB signaling pathway. MsrA-knockout (MsrA -/-) mice showed severely injured motor coordination, increased inflammation and oxidative stress [4].

In summary, MsrA plays essential roles in maintaining redox balance, cell migration, and tissue homeostasis. Through gene knockout studies in mouse models, its significance in cancer metastasis, atrial fibrillation, and demyelination has been revealed. Understanding MsrA's functions can provide new insights into the mechanisms of these diseases and potentially lead to novel therapeutic strategies.

References:

1. He, Dan, Feng, Huijin, Sundberg, Belen, Chang, Christopher J, Chio, Iok In Christine. 2022. Methionine oxidation activates pyruvate kinase M2 to promote pancreatic cancer metastasis. In Molecular cell, 82, 3045-3060.e11. doi:10.1016/j.molcel.2022.06.005. https://pubmed.ncbi.nlm.nih.gov/35752173/

2. Xu, Beibei, Xu, Yinli, Ren, Wenpu, Zhao, Jikai, Wang, Huishan. 2024. S-Methyl-L-cysteine targeting MsrA attenuates Ang II-induced oxidative stress and atrial remodeling via the p38 MAPK signaling pathway. In Food & function, 15, 9165-9175. doi:10.1039/d4fo03078h. https://pubmed.ncbi.nlm.nih.gov/39157962/

3. Tarafdar, Sreya, Kim, Geumsoo, Levine, Rodney L. 2018. Drosophila methionine sulfoxide reductase A (MSRA) lacks methionine oxidase activity. In Free radical biology & medicine, 131, 154-161. doi:10.1016/j.freeradbiomed.2018.12.001. https://pubmed.ncbi.nlm.nih.gov/30529269/

4. Fan, Hua, Li, Damiao, Guan, Xinlei, Ma, Ranran, Shu, Qing. 2020. MsrA Suppresses Inflammatory Activation of Microglia and Oxidative Stress to Prevent Demyelination via Inhibition of the NOX2-MAPKs/NF-κB Signaling Pathway. In Drug design, development and therapy, 14, 1377-1389. doi:10.2147/DDDT.S223218. https://pubmed.ncbi.nlm.nih.gov/32308370/

5. Chen, Yun, Zhao, Mingming, Lv, Mengli, Wang, Jin, Zuo, Kaijing. 2022. A Novel Small RNA, DsrO, in Deinococcus radiodurans Promotes Methionine Sulfoxide Reductase (msrA) Expression for Oxidative Stress Adaptation. In Applied and environmental microbiology, 88, e0003822. doi:10.1128/aem.00038-22. https://pubmed.ncbi.nlm.nih.gov/35575549/