Chaperone-mediated autophagy suppresses apoptosis via regulation of the unfolded protein response during chronic obstructive pulmonary disease pathogenesis

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

Research output: Contribution to journalArticlepeer-review

15 Citations (Scopus)

Abstract

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 UPRand 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.

Original languageEnglish
Pages (from-to)1256-1267
Number of pages12
JournalJournal of Immunology
Volume205
Issue number5
DOIs
Publication statusPublished - Sept 1 2020
Externally publishedYes

All Science Journal Classification (ASJC) codes

  • Immunology and Allergy
  • Immunology

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