CARD11-BCL10-MALT1 complex-dependent MALT1 activation facilitates myocardial oxidative stress in doxorubicin-treated mice via enhancing k48-linked ubiquitination of Nrf2

  • Antioxid Redox Signal. 2024 May 30. doi: 10.1089/ars.2023.0543.
Li-Qun Lu  1 ,  Ming-Rui Li  2 ,  Xu-Yan Liu  3 ,  Dan Peng  4 ,  Hong-Rui Liu  5 ,  Xiao-Jie Zhang  6 ,  Xiu-Ju Luo  7 ,  Jun Peng  8
Affiliations
  • 1. Central South University, Changsha, Hunan, China; [email protected].
  • 2. Central South University, Changsha, Hunan, China; [email protected].
  • 3. Central South University, Changsha, Hunan, China; [email protected].
  • 4. Central South University Third Xiangya Hospital, Changsha, Hunan, China; [email protected].
  • 5. Central South University Third Xiangya Hospital, Changsha, Hunan, China; [email protected].
  • 6. Central South University, Changsha, Hunan, China; [email protected].
  • 7. Central South University Third Xiangya Hospital, Changsha, Hunan, China; [email protected].
  • 8. Central South University, Department of Pharmacology, Xiangya School of Pharmaceutical Sciences, Changsha, China, 410078; [email protected].
PMID: 38814831 DOI: 10.1089/ars.2023.0543
Abstract

Aims: Down-regulation of nuclear factor erythroid 2-related factor 2 (Nrf2) contributes to doxorubicin (DOX)-induced myocardial oxidative stress, and inhibition of mucosa-associated lymphoid tissue lymphoma translocation protein 1 (MALT1) increased Nrf2 protein level in rat heart suffered ischemia/reperfusion, indicating a connection between MALT1 and Nrf2. This study aims to explore the role of MALT1 in DOX-induced myocardial oxidative stress and the underlying mechanisms.

Results: The mice received a single injection of DOX (15 mg/kg, i.p.) to induce myocardial oxidative stress, evidenced by increases in the levels of reactive oxidative species while decreases in the activities of anti-oxidative Enzymes, concomitant with a down-regulation of Nrf2; these phenomena were reversed by MALT1 Inhibitor. Similar phenomena were observed in DOX-induced oxidative stress in cardiomyocytes. Mechanistically, knockdown or inhibition of MALT1 notably attenuated the interaction between Nrf2 and MALT1, and decreased the k48-linked ubiquitination of Nrf2. Furthermore, inhibition or knockdown of calcium/calmodulin-dependent protein kinase II (CaMKII-δ) reduced the phosphorylation of Caspase recruitment domain-containing protein 11 (CARD11), and subsequently disrupted the assembly of CARD11, B-cell lymphoma 10 (BCL10) and MALT1 (CBM) complex, and reduced the MALT1-dependent k48-linked ubiquitination of Nrf2 in DOX-treated mice or cardiomyocytes.

Innovation and conclusion: The E3 ubiquitin Ligase function of MALT1 accounts for the down-regulation of Nrf2 and aggravation of myocardial oxidative stress in DOX-treated mice, and CaMKII-δ-dependent phosphorylation of CARD11 triggered the assembly of CBM complex and subsequent activation of MALT1.

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