Chaperone-Mediated Autophagy Suppresses Apoptosis via Regulation of the Unfolded Protein Response during Chronic Obstructive Pulmonary Disease Pathogenesis

Hosaka, Yusuke; Araya, Jun; Fujita, Yu; Kadota, Tsukasa; Tsubouchi, Kazuya; Yoshida, Masahiro; Minagawa, Shunsuke; Hara, Hiromichi; Kawamoto, Hironori; Watanabe, Naoaki; Ito, Akihiko; Ichikawa, Akihiro; Saito, Nayuta; Okuda, Kunio; Watanabe, Junko; Takekoshi, Daisuke; Utsumi, Hirofumi; Hashimoto, Mitsuo; Wakui, Hiroshi; Ito, Saburo; Numata, Takanori; Mori, Shiro; Matsudaira, Hideki; Hirano, Jun; Ohtsuka, Takashi; Nakayama, Katsutoshi; Kuwano, Kazuyoshi

doi:10.4049/jimmunol.2000132

Cited by 21 publications

(25 citation statements)

References 42 publications

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“…In addition, an inhibitory role for CMA in CS extract (CSE)-induced epithelial cell apoptosis has been reported for immortalized BEAS-2B bronchial epithelial cells [64]. Our in vitro experiments have shown that CSE induces CMA activation of LAMP2A expression through Nrf2-regulated transactivation [13]. CMA inhibition enhances the UPR, accompanied by increased apoptosis in response to CSE exposure, which is clearly reversed by LAMP2A overexpression in human bronchial epithelial cells (HBECs), indicating functional crosstalk between UPR and CMA during CSE exposure [13].…”

Section: Cma In Copd Pathogenesissupporting

confidence: 58%

“…A recent paper has demonstrated that Nrf2 upregulates LAMP2A expression levels by binding to the LAMP2A gene [25], which may at least partly explain the mechanism for CMA activation during oxidative stress. We have also detected the participation of Nrf2-mediated LAMP2A expression in cigarette smoke (CS)-induced CMA activation [13]. Alternatively, increase in LAMP2A levels is also mediated through alterations of protein stability in starvation conditions.…”

Section: Mechanisms Of Cmamentioning

confidence: 91%

“…We have also shown the potential participation of CMA in COPD through regulating the unfolded protein response (UPR) and apoptosis [13], indicating that CMA may have an important role in a variety of pulmonary pathogenesis. In this review, we initially summarize the general mechanism and role of CMA, and then describe the involvement of CMA in the pathogenesis of lung cancer and COPD.…”

Section: Introductionmentioning

confidence: 93%

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Role of chaperone-mediated autophagy in the pathophysiology including pulmonary disorders

et al. 2021

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Autophagy is a highly conserved mechanism of delivering cytoplasmic components for lysosomal degradation. Among the three major autophagic pathways, chaperone-mediated autophagy (CMA) is primarily characterized by its selective nature of protein degradation, which is mediated by heat shock cognate 71 kDa protein (HSC70: also known as HSPA8) recognition of the KFERQ peptide motif in target proteins. Lysosome-associated membrane protein type 2A (LAMP2A) is responsible for substrate binding and internalization to lysosomes, and thus, the lysosomal expression level of LAMP2A is a rate-limiting factor for CMA. Recent advances have uncovered not only physiological but also pathological role of CMA in multiple organs, including neurodegenerative disorders, kidney diseases, liver diseases, heart diseases, and cancers through the accumulation of unwanted proteins or increased degradation of target proteins with concomitant metabolic alterations resulting from CMA malfunction. With respect to pulmonary disorders, the involvement of CMA has been demonstrated in lung cancer and chronic obstructive pulmonary disease (COPD) pathogenesis through regulating apoptosis. Further understanding of CMA machinery may shed light on the molecular mechanisms of refractory disorders and lead to novel treatment modalities through CMA modulation.

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Section: Cma In Copd Pathogenesissupporting

confidence: 58%

Section: Mechanisms Of Cmamentioning

confidence: 91%

Section: Introductionmentioning

confidence: 93%

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Role of chaperone-mediated autophagy in the pathophysiology including pulmonary disorders

et al. 2021

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“…An annexin V-fluorescein isothiocyanate (FITC) apoptosis detection kit (BD Biosciences) was used for apoptosis evaluation as described previously [47]. Apoptotic cells were analyzed using a FACSCalibur flow cytometer (BD bioscience) and reported as the percentage of cells showing annexin V+/propidium iodide (PI)-and annexin V+/PI+.…”

Section: Isolation Of Neutrophils and Eosinophils And Western Blottingmentioning

confidence: 99%

Der f 38 Is a Novel TLR4-Binding Allergen Related to Allergy Pathogenesis from Dermatophagoides farinae

Kim

Hong

Kashif

et al. 2021

IJMS

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It is difficult to treat allergic diseases including asthma completely because its pathogenesis remains unclear. House dust mite (HDM) is a critical allergen and Toll-like receptor (TLR) 4 is a member of the toll-like receptor family, which plays an important role in allergic diseases. The purpose of this study was to characterize a novel allergen, Der f 38 binding to TLR4, and unveil its role as an inducer of allergy. Der f 38 expression was detected in the body and feces of Dermatophagoides farinae (DF). Electron microscopy revealed that it was located in the granule layer, the epithelium layer, and microvilli of the posterior midgut. The skin prick test showed that 60% of allergic subjects were Der f 38-positive. Der f 38 enhanced surface 203c expression in basophils of Der f 38-positive allergic subjects. By analysis of the model structure of Der p 38, the expected epitope sites are exposed on the exterior side. In animal experiments, Der f 38 triggered an infiltration of inflammatory cells. Intranasal (IN) administration of Der f 38 increased neutrophils in the lung. Intraperitoneal (IP) and IN injections of Der f 38 induced both eosinophils and neutrophils. Increased total IgE level and histopathological features were found in BALB/c mice treated with Der f 38 by IP and IN injections. TLR4 knockout (KO) BALB/c mice exhibited less inflammation and IgE level in the sera compared to wild type (WT) mice. Der f 38 directly binds to TLR4 using biolayer interferometry. Der f 38 suppressed the apoptosis of neutrophils and eosinophils by downregulating proteins in the proapoptotic pathway including caspase 9, caspase 3, and BAX and upregulating proteins in the anti-apoptotic pathway including BCL-2 and MCL-1. These findings might shed light on the pathogenic mechanisms of allergy to HDM.

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“…Interestingly, another form of autophagy known as chaperonemediated autophagy (CMA), which is LAMP2A facilitated selective degradation of proteins containing Lys-Phe-Gln-Arg-Gln (KFERQ) in the lysosomes mitigates cigarette smoke induced UPR and apoptosis (72).…”

Section: Chronic Obstructive Pulmonary Diseasementioning

confidence: 99%

Crosstalk Between ER Stress, Autophagy and Inflammation

2021

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The endoplasmic reticulum (ER) is not only responsible for protein synthesis and folding but also plays a critical role in sensing cellular stress and maintaining cellular homeostasis. Upon sensing the accumulation of unfolded proteins due to perturbation in protein synthesis or folding, specific intracellular signaling pathways are activated, which are collectively termed as unfolded protein response (UPR). UPR expands the capacity of the protein folding machinery, decreases protein synthesis and enhances ER-associated protein degradation (ERAD) which degrades misfolded proteins through the proteasomes. More recent evidences suggest that UPR also amplifies cytokines-mediated inflammatory responses leading to pathogenesis of inflammatory diseases. UPR signaling also activates autophagy; a lysosome-dependent degradative pathwaythat has an extended capacity to degrade misfolded proteins and damaged ER. Thus, activation of autophagy limits inflammatory response and provides cyto-protection by attenuating ER-stress. Here we review the mechanisms that couple UPR, autophagy and cytokine-induced inflammation that can facilitate the development of novel therapeutic strategies to mitigate cellular stress and inflammation associated with various pathologies.

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Chaperone-Mediated Autophagy Suppresses Apoptosis via Regulation of the Unfolded Protein Response during Chronic Obstructive Pulmonary Disease Pathogenesis

Cited by 21 publications

References 42 publications

Role of chaperone-mediated autophagy in the pathophysiology including pulmonary disorders

Role of chaperone-mediated autophagy in the pathophysiology including pulmonary disorders

Der f 38 Is a Novel TLR4-Binding Allergen Related to Allergy Pathogenesis from Dermatophagoides farinae

Crosstalk Between ER Stress, Autophagy and Inflammation

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