Thioredoxin 1 promotes autophagy through transnitrosylation of Atg7 during myocardial ischemia

Narayani Nagarajan, Shin Ichi Oka, Jihoon Nah, Changgong Wu, Peiyong Zhai, Risa Mukai, Xiaoyong Xu, Sanchita Kashyap, Chun Yang Huang, Eun Ah Sung, Wataru Mizushima, Allen Sam Titus, Koichiro Takayama, Youssef Mourad, Jamie Francisco, Tong Liu, Tong Chen, Hong Li, Junichi Sadoshima

Research output: Contribution to journalArticlepeer-review

11 Scopus citations

Abstract

Modification of cysteine residues by oxidative and nitrosative stress affects structure and function of proteins, thereby contributing to the pathogenesis of cardiovascular disease. Although the major function of thioredoxin 1 (Trx1) is to reduce disulfide bonds, it can also act as either a denitrosylase or transnitrosylase in a context-dependent manner. Here we show that Trx1 transnitrosylates Atg7, an E1-like enzyme, thereby stimulating autophagy. During ischemia, Trx1 was oxidized at Cys32-Cys35 of the oxidoreductase catalytic center and S-nitrosylated at Cys73. Unexpectedly, Atg7 Cys545-Cys548 reduced the disulfide bond in Trx1 at Cys32-Cys35 through thiol-disulfide exchange and this then allowed NO to be released from Cys73 in Trx1 and transferred to Atg7 at Cys402. Experiments conducted with Atg7 C402S–knockin mice showed that S-nitrosylation of Atg7 at Cys402 promotes autophagy by stimulating E1-like activity, thereby protecting the heart against ischemia. These results suggest that the thiol-disulfide exchange and the NO transfer are functionally coupled, allowing oxidized Trx1 to mediate a salutary effect during myocardial ischemia through transnitrosylation of Atg7 and stimulation of autophagy.

Original languageEnglish (US)
Article numbere162326
JournalJournal of Clinical Investigation
Volume133
Issue number3
DOIs
StatePublished - Feb 1 2023

All Science Journal Classification (ASJC) codes

  • General Medicine

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