bims-apauto 2022-09-11 papers

Issue of 2022–09–11
five papers selected by
Su Hyun Lee, Seoul National University

J Mol Cell Cardiol. 2022 Sep 06. pii: S0022-2828(22)00518-1. [Epub ahead of print]

The role of autophagic cell death in cardiac disease.

Jihoon Nah, Daniela Zablocki, Junichi Sadoshima.

Cardiomyocytes undergo various forms of cell death during heart disease such as myocardial infarction and heart failure. Understanding the mechanisms of cell death in cardiomyocytes is one of the most fundamental issues in the treatment of heart failure. Among the several kinds of cell death mechanisms, this review will focus on autophagy-related cardiomyocyte cell death. Although autophagy plays an essential role in mediating cellular quality control mechanisms for cell survival, dysregulation of autophagy can cause cell death, referred to as autophagy-dependent cell death or type II programmed cell death. The recent discovery of autosis as a modality of autophagy-dependent cell death with unique morphological and biochemical features has allowed us to broaden our understanding of the mechanistic role of autophagy in cell death. Here, we discuss autophagy-dependent cardiomyocyte cell death, including autosis, in pathophysiological conditions of the heart.

Keywords: Autophagy-dependent cell death; Autosis; Cardiovascular disease; Therapeutic interventions

DOI: https://doi.org/10.1016/j.yjmcc.2022.08.362

Front Immunol. 2022 ;13 963955

Dysregulation of neutrophil death in sepsis.

Cheng-Long Zhu, Yi Wang, Qiang Liu, Hui-Ru Li, Chang-Meng Yu, Peng Li, Xiao-Ming Deng, Jia-Feng Wang.

Sepsis is a prevalent disease that has alarmingly high mortality rates and, for several survivors, long-term morbidity. The modern definition of sepsis is an aberrant host response to infection followed by a life-threatening organ dysfunction. Sepsis has a complicated pathophysiology and involves multiple immune and non-immune mediators. It is now believed that in the initial stages of sepsis, excessive immune system activation and cascading inflammation are usually accompanied by immunosuppression. During the pathophysiology of severe sepsis, neutrophils are crucial. Recent researches have demonstrated a clear link between the process of neutrophil cell death and the emergence of organ dysfunction in sepsis. During sepsis, spontaneous apoptosis of neutrophils is inhibited and neutrophils may undergo some other types of cell death. In this review, we describe various types of neutrophil cell death, including necrosis, apoptosis, necroptosis, pyroptosis, NETosis, and autophagy, to reveal their known effects in the development and progression of sepsis. However, the exact role and mechanisms of neutrophil cell death in sepsis have not been fully elucidated, and this remains a major challenge for future neutrophil research. We hope that this review will provide hints for researches regarding neutrophil cell death in sepsis and provide insights for clinical practitioners.

Keywords: NETs; apoptosis; autophagy; cell death; necroptosis; neutrophil; pyroptosis; sepsis

DOI: https://doi.org/10.3389/fimmu.2022.963955

Nat Commun. 2022 Sep 03. 13(1): 5204

Suppression of ACE2 SUMOylation protects against SARS-CoV-2 infection through TOLLIP-mediated selective autophagy.

Shouheng Jin, Xing He, Ling Ma, Zhen Zhuang, Yiliang Wang, Meng Lin, Sihui Cai, Lu Wei, Zheyu Wang, Zhiyao Zhao, Yaoxing Wu, Lin Sun, Chunwei Li, Weihong Xie, Yong Zhao, Zhou Songyang, Ke Peng, Jincun Zhao, Jun Cui.

In addition to investigating the virology of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), discovering the host-virus dependencies are essential to identify and design effective antiviral therapy strategy. Here, we report that the SARS-CoV-2 entry receptor, ACE2, conjugates with small ubiquitin-like modifier 3 (SUMO3) and provide evidence indicating that prevention of ACE2 SUMOylation can block SARS-CoV-2 infection. E3 SUMO ligase PIAS4 prompts the SUMOylation and stabilization of ACE2, whereas deSUMOylation enzyme SENP3 reverses this process. Conjugation of SUMO3 with ACE2 at lysine (K) 187 hampers the K48-linked ubiquitination of ACE2, thus suppressing its subsequent cargo receptor TOLLIP-dependent autophagic degradation. TOLLIP deficiency results in the stabilization of ACE2 and elevated SARS-CoV-2 infection. In conclusion, our findings suggest selective autophagic degradation of ACE2 orchestrated by SUMOylation and ubiquitination as a potential way to combat SARS-CoV-2 infection.

DOI: https://doi.org/10.1038/s41467-022-32957-y

Mini Rev Med Chem. 2022 Sep 05.

Relationship between Autophagy and Drug Resistance in Tumors.

Xuan Hu, Lu Wen, Xianfeng Li, Chuanying Zhu.

Multidrug resistance (MDR) in tumor cells, a phenomenon in which tumor cells become resistant to chemotherapeutic drugs with different chemical structures and mechanisms of action, is a major obstacle to tumor therapy and is an urgent problem to be addressed. Autophagy, widely found in eukaryotic cells, is a lysosome-dependent pathway of self-degradation. In different environments, autophagy can play different roles in the self-protection of cells. At different stages of tumorigenesis, autophagy can play two distinct roles: inhibition of cancer and promotion of cancer. The relationship between autophagy and drug resistance in tumor cells is complex. Moreover, autophagy can play a role in promoting drug resistance and drug sensitivity through different molecular pathways. This study aimed to investigate the relationship between autophagy and drug resistance in tumor cells from the perspective of molecular mechanisms.

Keywords: Autophagy; Chemotherapy; MDR; Self-protection; Tumorigenesis; drug sensitivity

DOI: https://doi.org/10.2174/1389557522666220905090732

Front Physiol. 2022 ;13 957968

Mitophagy: A potential therapeutic target for insulin resistance.

Peng Ning, Xiaobo Jiang, Jing Yang, Jiaxing Zhang, Fan Yang, Hongyi Cao.

Glucose and lipid metabolism disorders caused by insulin resistance (IR) can lead to metabolic disorders such as diabetes, obesity, and the metabolic syndrome. Early and targeted intervention of IR is beneficial for the treatment of various metabolic disorders. Although significant progress has been made in the development of IR drug therapies, the state of the condition has not improved significantly. There is a critical need to identify novel therapeutic targets. Mitophagy is a type of selective autophagy quality control system that is activated to clear damaged and dysfunctional mitochondria. Mitophagy is highly regulated by various signaling pathways, such as the AMPK/mTOR pathway which is involved in the initiation of mitophagy, and the PINK1/Parkin, BNIP3/Nix, and FUNDC1 pathways, which are involved in mitophagosome formation. Mitophagy is involved in numerous human diseases such as neurological disorders, cardiovascular diseases, cancer, and aging. However, recently, there has been an increasing interest in the role of mitophagy in metabolic disorders. There is emerging evidence that normal mitophagy can improve IR. Unfortunately, few studies have investigated the relationship between mitophagy and IR. Therefore, we set out to review the role of mitophagy in IR and explore whether mitophagy may be a potential new target for IR therapy. We hope that this effort serves to stimulate further research in this area.

Keywords: autophagy; insulin resistance; mitochondrial dysfunction; mitophagy; therapeutic target

DOI: https://doi.org/10.3389/fphys.2022.957968