PINK1 and PARK2 Suppress Pancreatic Tumorigenesis through Control of Mitochondrial Iron-Mediated Immunometabolism

Li, Changfeng; Zhang, Ying; Cheng, Xing; Yuan, Hua; Zhu, Shan; Liu, Jiao; Wen, Qirong; Xie, Yangchun; Liu, Jinbao; Kroemer, Guido; Klionsky, Daniel J.; Lotze, Michael T.; Zeh, Herbert J.; Kang, Rui; Tang, Daolin

doi:10.1016/j.devcel.2018.07.012

Cited by 179 publications

(162 citation statements)

References 42 publications

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“…). A recent study has shown that AIM2 inflammasome‐mediated HMGB1 release can induce PD‐L1 expression in tumor cells and results in immunosuppression in tumor microenvironment . However, it remains to be determined whether HMGB1 can also induce PD‐L1 expression in some cell types during sepsis and trauma.…”

Section: Redox Regulation Of Hmgb1 Functionmentioning

confidence: 99%

Location is the key to function: HMGB1 in sepsis and trauma-induced inflammation

Deng

Scott

Fan

et al. 2019

Journal of Leukocyte Biology

116

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High mobility group box 1 (HMGB1) is a multifunctional nuclear protein, probably known best as a prototypical alarmin or damage-associated molecular pattern (DAMP) molecule when released from cells. However, HMGB1 has multiple functions that depend on its location in the nucleus, in the cytosol, or extracellularly after either active release from cells, or passive release upon lytic cell death. Movement of HMGB1 between cellular compartments is a dynamic process induced by a variety of cell stresses and disease processes, including sepsis, trauma, and hemorrhagic shock.Location of HMGB1 is intricately linked with its function and is regulated by a series of posttranslational modifications. HMGB1 function is also regulated by the redox status of critical cysteine residues within the protein, and is cell-type dependent. This review highlights some of the mechanisms that contribute to location and functions of HMGB1, and focuses on some recent insights on important intracellular effects of HMGB1 during sepsis and trauma. K E Y W O R D S AIM2, autophagy, caspase-11, DAMPs, pyroptosis 2 NUCLEAR-TO-CYTOPLASM SHUTTLING OF HMGB1 HMGB1 consists of 215 aa residues, and contains 2 HMG DNAbinding domains, designated as A and B boxes, together with a negatively charged C-terminal acidic region. 14 Two nuclear localization sites (NLSs), one located in the A box (aa 28-44) and one in the B box (aa 179-185), control the nuclear localization of HMGB1 under homeostatic states. 14 Posttranslational modifications of NLS sites, including acetylation, phosphorylation, and methylation, regulate the ability of HMGB1 to translocate to the cytoplasm during cellular stress.Once in the cytoplasm HMGB1 can affect multiple inflammatory responses, and can be actively released into the extracellular space and circulation.

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Section: Redox Regulation Of Hmgb1 Functionmentioning

confidence: 99%

Location is the key to function: HMGB1 in sepsis and trauma-induced inflammation

Deng

Scott

Fan

et al. 2019

Journal of Leukocyte Biology

116

View full text Add to dashboard Cite

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“…Increased production of IL‐1α from immunosuppressive tumor‐associated plasmacytoid dendritic cells (pDCs) in lung cancer depends on the AIM2 inflammasome . Disrupted mitochondrial iron metabolism in the absence of the mitophagy proteins PINK1 and PARK2 induces AIM2‐dependent high mobility group box 1 release in pancreatic ductal adenocarcinoma, promoting the upregulation of immune checkpoint protein programmed cell death ligand 1 . These two studies highlight the significance of understudied AIM2–mediated alarmins in tumorigenesis.…”

Section: Role Of Aim2 In Sterile Inflammatory Diseasesmentioning

confidence: 95%

Role of AIM2 inflammasome in inflammatory diseases, cancer and infection

2019

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AIM2 is a cytosolic innate immune receptor which recognizes double-stranded DNA (dsDNA) released during cellular perturbation and pathogenic assault. AIM2 recognition of dsDNA leads to the assembly of a large multiprotein oligomeric complex termed the inflammasome. This inflammasome assembly leads to the secretion of bioactive interleukin-1β (IL-1β) and IL-18 and induction of an inflammatory form of cell death called pyroptosis. Sensing of dsDNA by AIM2 in the cytosol is crucial to mediate protection against the invading pathogens including bacteria, virus, fungi and parasites. AIM2 also responds to dsDNA released from damaged host cells, resulting in the secretion of the effector cytokines thereby driving the progression of sterile inflammatory diseases such as skin disease, neuronal disease, chronic kidney disease, cardiovascular disease and diabetes. Additionally, the protection mediated by AIM2 in the development of colorectal cancer depends on its ability to regulate epithelial cell proliferation and gut microbiota in maintaining intestinal homeostasis independently of the effector cytokines. In this review, we will highlight the recent progress on the role of the AIM2 inflammasome as a guardian of cellular integrity in modulating chronic inflammatory diseases, cancer and infection.Keywords: AIM2 r cell death r gasdermin r inflammasome r pyroptosis

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“…In Park2 knock-out mouse models, the resulting oxidative stress and the Warburg effect [130] caused an increase in the mRNA of Aim2, a protein involved in cytokine production [131]. In these mouse models, activation of Aim2 ultimately led to upregulation of PD-L1 in pancreatic tumors and lower rates of survival, an effect seen in human pancreatic tumors and patients [131]. Thus, Park2's roles in metabolism may affect the ability of the immune system to regulate cancer progression.…”

Section: Othermentioning

confidence: 99%

E3 Ubiquitin Ligases in Cancer and Their Pharmacological Targeting

Ong¹,

Torres²

2019

Ubiquitin Proteasome System - Current Insights Into Mechanism Cellular Regulation and Disease

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Ubiquitination plays many critical roles in protein function and regulation. Consequently, mutation and aberrant expression of E3 ubiquitin ligases can drive cancer progression. Identifying key ligase-substrate relationships is crucial to understanding the molecular basis and pathways behind cancer and toward identifying novel targets for cancer therapeutics. Here, we review the importance of E3 ligases in the regulating the hallmarks of cancer, discuss some of the key and novel E3 ubiquitin ligases that drive tumor formation and angiogenesis, and review the clinical development of inhibitors that antagonize their function. We conclude with perspectives on the field and future directions toward understanding ubiquitination and cancer progression.

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PINK1 and PARK2 Suppress Pancreatic Tumorigenesis through Control of Mitochondrial Iron-Mediated Immunometabolism

Cited by 179 publications

References 42 publications

Location is the key to function: HMGB1 in sepsis and trauma-induced inflammation

Location is the key to function: HMGB1 in sepsis and trauma-induced inflammation

Role of AIM2 inflammasome in inflammatory diseases, cancer and infection

E3 Ubiquitin Ligases in Cancer and Their Pharmacological Targeting

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