PMID- 32699159 OWN - NLM STAT- MEDLINE DCOM- 20210322 LR - 20231213 IS - 1550-6606 (Electronic) IS - 0022-1767 (Linking) VI - 205 IP - 5 DP - 2020 Sep 1 TI - Chaperone-Mediated Autophagy Suppresses Apoptosis via Regulation of the Unfolded Protein Response during Chronic Obstructive Pulmonary Disease Pathogenesis. PG - 1256-1267 LID - 10.4049/jimmunol.2000132 [doi] AB - Cigarette smoke (CS) induces accumulation of misfolded proteins with concomitantly enhanced unfolded protein response (UPR). Increased apoptosis linked to UPR has been demonstrated in chronic obstructive pulmonary disease (COPD) pathogenesis. Chaperone-mediated autophagy (CMA) is a type of selective autophagy for lysosomal degradation of proteins with the KFERQ peptide motif. CMA has been implicated in not only maintaining nutritional homeostasis but also adapting the cell to stressed conditions. Although recent papers have shown functional cross-talk between UPR and CMA, mechanistic implications for CMA in COPD pathogenesis, especially in association with CS-evoked UPR, remain obscure. In this study, we sought to examine the role of CMA in regulating CS-induced apoptosis linked to UPR during COPD pathogenesis using human bronchial epithelial cells (HBEC) and lung tissues. CS extract (CSE) induced LAMP2A expression and CMA activation through a Nrf2-dependent manner in HBEC. LAMP2A knockdown and the subsequent CMA inhibition enhanced UPR, including CHOP expression, and was accompanied by increased apoptosis during CSE exposure, which was reversed by LAMP2A overexpression. Immunohistochemistry showed that Nrf2 and LAMP2A levels were reduced in small airway epithelial cells in COPD compared with non-COPD lungs. Both Nrf2 and LAMP2A levels were significantly reduced in HBEC isolated from COPD, whereas LAMP2A levels in HBEC were positively correlated with pulmonary function tests. These findings suggest the existence of functional cross-talk between CMA and UPR during CSE exposure and also that impaired CMA may be causally associated with COPD pathogenesis through enhanced UPR-mediated apoptosis in epithelial cells. CI - Copyright (c) 2020 by The American Association of Immunologists, Inc. FAU - Hosaka, Yusuke AU - Hosaka Y AD - Division of Respiratory Diseases, Department of Internal Medicine, Jikei University School of Medicine, Tokyo 104-8461, Japan. FAU - Araya, Jun AU - Araya J AD - Division of Respiratory Diseases, Department of Internal Medicine, Jikei University School of Medicine, Tokyo 104-8461, Japan; araya@jikei.ac.jp. FAU - Fujita, Yu AU - Fujita Y AUID- ORCID: 0000-0002-8916-7303 AD - Division of Respiratory Diseases, Department of Internal Medicine, Jikei University School of Medicine, Tokyo 104-8461, Japan. FAU - Kadota, Tsukasa AU - Kadota T AD - Division of Respiratory Diseases, Department of Internal Medicine, Jikei University School of Medicine, Tokyo 104-8461, Japan. FAU - Tsubouchi, Kazuya AU - Tsubouchi K AUID- ORCID: 0000-0003-0145-8745 AD - Division of Respiratory Diseases, Department of Internal Medicine, Jikei University School of Medicine, Tokyo 104-8461, Japan. FAU - Yoshida, Masahiro AU - Yoshida M AD - Division of Respiratory Diseases, Department of Internal Medicine, Jikei University School of Medicine, Tokyo 104-8461, Japan. FAU - Minagawa, Shunsuke AU - Minagawa S AUID- ORCID: 0000-0003-1732-4856 AD - Division of Respiratory Diseases, Department of Internal Medicine, Jikei University School of Medicine, Tokyo 104-8461, Japan. FAU - Hara, Hiromichi AU - Hara H AD - Division of Respiratory Diseases, Department of Internal Medicine, Jikei University School of Medicine, Tokyo 104-8461, Japan. FAU - Kawamoto, Hironori AU - Kawamoto H AD - Division of Respiratory Diseases, Department of Internal Medicine, Jikei University School of Medicine, Tokyo 104-8461, Japan. FAU - Watanabe, Naoaki AU - Watanabe N AD - Division of Respiratory Diseases, Department of Internal Medicine, Jikei University School of Medicine, Tokyo 104-8461, Japan. FAU - Ito, Akihiko AU - Ito A AUID- ORCID: 0000-0001-5783-5998 AD - Division of Respiratory Diseases, Department of Internal Medicine, Jikei University School of Medicine, Tokyo 104-8461, Japan. FAU - Ichikawa, Akihiro AU - Ichikawa A AD - Division of Respiratory Diseases, Department of Internal Medicine, Jikei University School of Medicine, Tokyo 104-8461, Japan. FAU - Saito, Nayuta AU - Saito N AUID- ORCID: 0000-0002-9314-4745 AD - Division of Respiratory Diseases, Department of Internal Medicine, Jikei University School of Medicine, Tokyo 104-8461, Japan. FAU - Okuda, Keitaro AU - Okuda K AD - Division of Respiratory Diseases, Department of Internal Medicine, Jikei University School of Medicine, Tokyo 104-8461, Japan. FAU - Watanabe, Junko AU - Watanabe J AD - Division of Respiratory Diseases, Department of Internal Medicine, Jikei University School of Medicine, Tokyo 104-8461, Japan. FAU - Takekoshi, Daisuke AU - Takekoshi D AD - Division of Respiratory Diseases, Department of Internal Medicine, Jikei University School of Medicine, Tokyo 104-8461, Japan. FAU - Utsumi, Hirofumi AU - Utsumi H AD - Division of Respiratory Diseases, Department of Internal Medicine, Jikei University School of Medicine, Tokyo 104-8461, Japan. FAU - Hashimoto, Mitsuo AU - Hashimoto M AD - Division of Respiratory Diseases, Department of Internal Medicine, Jikei University School of Medicine, Tokyo 104-8461, Japan. FAU - Wakui, Hiroshi AU - Wakui H AD - Division of Respiratory Diseases, Department of Internal Medicine, Jikei University School of Medicine, Tokyo 104-8461, Japan. FAU - Ito, Saburo AU - Ito S AD - Division of Respiratory Diseases, Department of Internal Medicine, Jikei University School of Medicine, Tokyo 104-8461, Japan. FAU - Numata, Takanori AU - Numata T AUID- ORCID: 0000-0003-2784-2331 AD - Division of Respiratory Diseases, Department of Internal Medicine, Jikei University School of Medicine, Tokyo 104-8461, Japan. FAU - Mori, Shohei AU - Mori S AD - Division of Chest Diseases, Department of Surgery, Jikei University School of Medicine, Tokyo 104-8461, Japan; and. FAU - Matsudaira, Hideki AU - Matsudaira H AUID- ORCID: 0000-0002-8817-275X AD - Division of Chest Diseases, Department of Surgery, Jikei University School of Medicine, Tokyo 104-8461, Japan; and. FAU - Hirano, Jun AU - Hirano J AD - Division of Chest Diseases, Department of Surgery, Jikei University School of Medicine, Tokyo 104-8461, Japan; and. FAU - Ohtsuka, Takashi AU - Ohtsuka T AUID- ORCID: 0000-0002-8039-9159 AD - Division of Chest Diseases, Department of Surgery, Jikei University School of Medicine, Tokyo 104-8461, Japan; and. FAU - Nakayama, Katsutoshi AU - Nakayama K AUID- ORCID: 0000-0002-0141-7081 AD - Department of Respiratory Medicine, Akita University Graduate School of Medicine, Akita 010-8543, Japan. FAU - Kuwano, Kazuyoshi AU - Kuwano K AUID- ORCID: 0000-0003-0551-7386 AD - Division of Respiratory Diseases, Department of Internal Medicine, Jikei University School of Medicine, Tokyo 104-8461, Japan. LA - eng PT - Journal Article PT - Research Support, Non-U.S. Gov't DEP - 20200722 PL - United States TA - J Immunol JT - Journal of immunology (Baltimore, Md. : 1950) JID - 2985117R RN - 0 (NF-E2-Related Factor 2) RN - 0 (Smoke) SB - IM MH - Apoptosis/*physiology MH - Cells, Cultured MH - Chaperone-Mediated Autophagy/*physiology MH - Epithelial Cells/metabolism/pathology MH - Humans MH - Lung/metabolism/pathology MH - Lysosomes/metabolism/pathology MH - NF-E2-Related Factor 2/metabolism MH - Pulmonary Disease, Chronic Obstructive/metabolism/*pathology MH - Smoke/adverse effects MH - Nicotiana/adverse effects MH - Unfolded Protein Response/*physiology EDAT- 2020/07/24 06:00 MHDA- 2021/03/23 06:00 CRDT- 2020/07/24 06:00 PHST- 2020/02/05 00:00 [received] PHST- 2020/06/29 00:00 [accepted] PHST- 2020/07/24 06:00 [pubmed] PHST- 2021/03/23 06:00 [medline] PHST- 2020/07/24 06:00 [entrez] AID - jimmunol.2000132 [pii] AID - 10.4049/jimmunol.2000132 [doi] PST - ppublish SO - J Immunol. 2020 Sep 1;205(5):1256-1267. doi: 10.4049/jimmunol.2000132. Epub 2020 Jul 22.