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Original Research ARTICLE Provisionally accepted The full-text will be published soon. Notify me

Front. Physiol. | doi: 10.3389/fphys.2019.01089

A unique SUMO-interacting motif of Trx2 is critical for its mitochondrial presequence processing and anti-oxidant activity

 Chaofei Chen1, Kang Wang1, Haifeng Zhang1, Huanjiao J. Zhou1,  Yuxin Chen2 and  Wang Min1, 3*
  • 1School of Medicine, Yale University, United States
  • 2Medical School, Nanjing University, China
  • 3Pathology, Yale University, United States

Objective: Mitochondrial thioredoxin 2 (Trx2) is a vital mitochondrial redox protein that mediates normal protein thiol reduction and provides electrons to peroxiredoxin 3 (Prx3) to scavenge H2O2 in mitochondria. It has been widely reported that Trx2 deletion in cells or mice generates massive reactive oxygen species (ROS) which have been implicated in many pathological processes. On the contrary, how ROS regulate Trx2 expression and activity remains to be elucidated.

Approach and Results: Here we show that excess ROS induce endothelial cell senescence concomitant with an attenuation of Trx2 processing in which Trx2 presequence (i.e., mitochondrial targeting signal peptide (MTS)) is cleaved to generate a mature form. Mutation analyses indicate that Trx2 processing is mediated by mitochondrial processing peptidase (MPP) and mitochondrial intermediate peptidase (MIP)-recognition sites within the MTS. Interestingly, a mutation at a SUMO- interacting motif (SIM), but not the catalytic sites within the mature Trx2 protein, completely blocks Trx2 processing with no effect on Trx2 mitochondrial targeting. Consistently, chemical inhibition of protein SUMOylation attenuates, while SUMOylation agonist promotes, Trx2 processing. Moreover, we identify the MPP subunit is a SUMOylated protein that potentially mediates Trx2-binding and cleavage. Furthermore, the unprocessed form of Trx2-SIM is unable to protect cells from both ROS generation and oxidative stress-induced cellular senescence.
Conclusion: Our study reveals that a unique SUMO-interacting motif of Trx2 is critical for its mitochondrial processing and subsequent anti-oxidant/antisenescence activities.

Keywords: Thioredoxin-2, Mitochondria, Sumoylation, SUMO-interacting Motif (SIM), senescence

Received: 11 Apr 2019; Accepted: 07 Aug 2019.

Copyright: © 2019 Chen, Wang, Zhang, Zhou, Chen and Min. This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.

* Correspondence: Prof. Wang Min, School of Medicine, Yale University, New Haven, 06510, Connecticut, United States, wang.min@yale.edu