Peroxiredoxin-mediated disulfide bond formation is required for nucleocytoplasmic translocation and secretion of HMGB1 in response to inflammatory stimuli

Kwak, Man Sup; Kim, Hee Sue; Lkhamsuren, Khulan; Kim, Young Hun; Han, Myeong Gil; Shin, Jae Min; Rhee, Woo Joong; Lee, Se Kyoung; Rhee, Sue Goo; Shin, Jeon-Soo

doi:10.1016/j.redox.2019.101203

Cited by 47 publications

(61 citation statements)

References 48 publications

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“…Hence, the avoidance of the ER limits HMGB1 oxidation. Conversely, a recent study indicates that HMGB1 oxidation can occur in the nucleus of mouse bone marrow-derived macrophages, mouse embryonic fibroblasts and HEK293T cells (34). The authors demonstrate that disulphide bond formation is required for HMGB1 nucleocytoplasmic translocation and secretion, and is mediated by peroxiredoxins (Prxs), a ubiquitous family of antioxidant enzymes highly expressed in cells.…”

Section: Discussionmentioning

confidence: 99%

Oxidation of HMGB1 Is a Dynamically Regulated Process in Physiological and Pathological Conditions

Ferrara¹,

Chialli²,

Ferreira³

et al. 2020

Front. Immunol.

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Acute inflammation is a complex biological response of tissues to harmful stimuli, such as pathogens or cell damage, and is essential for immune defense and proper healing. However, unresolved inflammation can lead to chronic disorders, including cancer and fibrosis. The High Mobility Group Box 1 (HMGB1) protein is a Damage-Associated Molecular Pattern (DAMP) molecule that orchestrates key events in inflammation by switching among mutually exclusive redox states. Fully reduced HMGB1 (frHMGB1) supports immune cell recruitment and tissue regeneration, while the isoform containing a disulphide bond (dsHMGB1) promotes secretion of inflammatory mediators by immune cells. Although it has been suggested that the tissue itself determines the redox state of the extracellular space and of released HMGB1, the dynamics of HMGB1 oxidation in health and disease are unknown. In the present work, we analyzed the expression of HMGB1 redox isoforms in different inflammatory conditions in skeletal muscle, from acute injury to muscle wasting, in tumor microenvironment, in spleen, and in liver after drug intoxication. Our results reveal that the redox modulation of HMGB1 is tissue-specific, with high expression of dsHMGB1 in normal spleen and liver and very low in muscle, where it appears after acute damage. Similarly, dsHMGB1 is highly expressed in the tumor microenvironment while it is absent in cachectic muscles from the same tumorbearing mice. These findings emphasize the accurate and dynamic regulation of HMGB1 redox state, with the presence of dsHMGB1 tightly associated with leukocyte infiltration. Accordingly, we identified circulating, infiltrating, and resident leukocytes as reservoirs and transporters of dsHMGB1 in tissue and tumor microenvironment, demonstrating that the redox state of HMGB1 is controlled at both tissue and cell levels. Overall, our data point out that HMGB1 oxidation is a timely and spatially regulated process in physiological and pathological conditions. This precise modulation might play key roles to finetune inflammatory and regenerative processes.

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Section: Discussionmentioning

confidence: 99%

Oxidation of HMGB1 Is a Dynamically Regulated Process in Physiological and Pathological Conditions

Ferrara¹,

Chialli²,

Ferreira³

et al. 2020

Front. Immunol.

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“…The formation of the disulfide bond is sufficient for HMGB1 secretion and secreted HMGB1 signals danger to surrounding cells. HMGB1 secretion induced by LPS is attenuated in macrophages isolated from Prdx1or Prdx2-knockout mice [35].…”

Section: Inflammationmentioning

confidence: 95%

“…PRDX1 is a negative regulator of Th2-type allergic asthma that is induced by ovalbumin [25]. Inflammatory stimuli produce the intramolecular disulfide bond in HMGB1, which is mediated by PRDX1 or PRDX2 [35]. The formation of the disulfide bond is sufficient for HMGB1 secretion and secreted HMGB1 signals danger to surrounding cells.…”

Section: Inflammationmentioning

confidence: 99%

Knockout Mouse Models for Peroxiredoxins

Lee

2020

Antioxidants

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Peroxiredoxins (PRDXs) are members of a highly conserved peroxidase family and maintain intracellular reactive oxygen species (ROS) homeostasis. The family members are expressed in most organisms and involved in various biological processes, such as cellular protection against ROS, inflammation, carcinogenesis, atherosclerosis, heart diseases, and metabolism. In mammals, six PRDX members have been identified and are subdivided into three subfamilies: typical 2-Cys (PRDX1, PRDX2, PRDX3, and PRDX4), atypical 2-Cys (PRDX5), and 1-Cys (PRDX6) subfamilies. Knockout mouse models of PRDXs have been developed to investigate their in vivo roles. This review presents an overview of the knockout mouse models of PRDXs with emphases on the biological and physiological changes of these model mice.

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“…Nuclear HMGB1 is translocated to the cytoplasm by HSP90AA1 and XPO1. Furthermore, post-translational modifications of HMGB1, such as oxidation, helps its binding to XPO1 [27,48]. Cytoplasmic HMGB1 activates autophagy [48][49][50], and this autophagy activation induces the extracellular secretion of HMGB1.…”

Section: Physiological Relevance and Proposed Model Of Hmgb1 Secretionmentioning

confidence: 99%

Secretory autophagy machinery and vesicular trafficking are involved in HMGB1 secretion

et al. 2020

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Nuclear protein HMGB1 is secreted in response to various stimuli and functions as a danger-associated molecular pattern. Extracellular HMGB1 induces inflammation, cytokine production, and immune cell recruitment via activation of various receptors. As HMGB1 does not contain an endoplasmic reticulumtargeting signal peptide, HMGB1 is secreted via the endoplasmic reticulum-Golgi independently via an unconventional secretion pathway. However, the mechanism underlying HMGB1 secretion remains largely unknown. Here, we investigated the role of secretory autophagy machinery and vesicular trafficking in HMGB1 secretion. We observed that HSP90AA1 (heat shock protein 90 alpha family class A member 1), a stress-inducible protein, regulates the translocation of HMGB1 from the nucleus to the cytoplasm and its secretion through direct interaction. Additionally, geldanamycin, an HSP90AA1 inhibitor, reduced HMGB1 secretion. GORASP2/GRASP55 (golgi reassembly stacking protein 2), ARF1 Q71L (ADP ribosylation factor 1), and SAR1A T39N (secretion associated Ras related GTPase 1A), which promoted unconventional protein secretion, increased HMGB1 secretion. HMGB1 secretion was inhibited by an early autophagy inhibitor and diminished in ATG5-deficient cells even when GORASP2 was overexpressed. In contrast, a late autophagy inhibitor increased HMGB1 secretion under the same conditions. The multivesicular body formation inhibitor GW4869 dramatically decreased HMGB1 secretion under HMGB1 secretion-inducing conditions. Thus, we demonstrated that secretory autophagy and multivesicular body formation mediate HMGB1 secretion.

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Peroxiredoxin-mediated disulfide bond formation is required for nucleocytoplasmic translocation and secretion of HMGB1 in response to inflammatory stimuli

Cited by 47 publications

References 48 publications

Oxidation of HMGB1 Is a Dynamically Regulated Process in Physiological and Pathological Conditions

Oxidation of HMGB1 Is a Dynamically Regulated Process in Physiological and Pathological Conditions

Knockout Mouse Models for Peroxiredoxins

Secretory autophagy machinery and vesicular trafficking are involved in HMGB1 secretion

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