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A triterpenoid Nrf2 activator, RS9, promotes LC3-associated phagocytosis of photoreceptor outer segments in a p62-independent manner.
Free Radic Biol Med. 2020 Mar 23; 152:235-247.FR

Abstract

Daily phagocytosis of shed photoreceptor outer segments (POS) by the retinal pigment epithelium (RPE) is required to sustain the visual function. Recent reports revealed that POS phagocytosis is progressed with LC3-associated manner. Patients with age-related macular degeneration (AMD) had impaired autophagic degradation in the RPE. Nrf2 is a key antioxidant transcriptional regulator that ameliorates oxidative stress which is another contributor to AMD pathogenesis. Nrf2 activation also induces the autophagy receptor protein, p62. However, the role of the Nrf2-p62 pathway in LC3-associated phagocytosis of POS is poorly understood. Here, we investigated the relationships between Nrf2 activation and POS phagocytosis progression. A triterpenoid Nrf2 activator, RS9, facilitated POS uptake into phagolysosomes in RPE cells. RS9 also induced the expression of the autophagy-related proteins, LC3-II and p62, as well as phase-2 antioxidant enzymes. The effect of RS9 on POS phagocytosis was abolished by autophagy inhibition. Unexpectedly, p62 knockdown did not inhibit the effect of RS9 on POS phagocytosis, although, RS9-mediated LC3-II induction by RS9 was inhibited in p62 knockdown RPE cells. We also found that RS9 activated the AMPKα-mTOR signaling pathway earlier than p62 induction. Knockdown of AMPKα1, but not α2, inhibited the RS9-mediated activation of LC3-associated phagocytosis and RS9-mediated induction of LC3-II. Furthermore, intravitreal treatment of RS9 to adult mice decreased the size of POS phagolysosomes after light exposure. Collectively, these results showed that RS9-mediated activation of POS phagocytosis was mainly ascribed to the enhancement of autophagy via AMPKα1 activation. Our findings reveal novel effects of Nrf2 and AMPK α1 activation that contribute to the maintenance of the RPE function via LC3-associated POS phagocytosis.

Authors+Show Affiliations

Molecular Pharmacology, Department of Biofunctional Evaluation, Gifu Pharmaceutical University, Gifu, Japan. Electronic address: saito.yakkou@gmail.com.Molecular Pharmacology, Department of Biofunctional Evaluation, Gifu Pharmaceutical University, Gifu, Japan. Electronic address: yako.yakkou@gmail.com.Department of Biomedical Research Laboratory, Gifu Pharmaceutical University, Gifu, Japan. Electronic address: otsu-wa@gifu-pu.ac.jp.Molecular Pharmacology, Department of Biofunctional Evaluation, Gifu Pharmaceutical University, Gifu, Japan. Electronic address: nakamuras@gifu-pu.ac.jp.Molecular Pharmacology, Department of Biofunctional Evaluation, Gifu Pharmaceutical University, Gifu, Japan. Electronic address: inoue.yakkou@gmail.com.Molecular Pharmacology, Department of Biofunctional Evaluation, Gifu Pharmaceutical University, Gifu, Japan. Electronic address: muramatsu.yakkou@gmail.com.Daiichi Sankyo Co. Ltd., Tokyo, Japan. Electronic address: nakagami.yasuhiro.y4@daiichisankyo.co.jp.Molecular Pharmacology, Department of Biofunctional Evaluation, Gifu Pharmaceutical University, Gifu, Japan; Department of Biomedical Research Laboratory, Gifu Pharmaceutical University, Gifu, Japan. Electronic address: shimazawa@gifu-pu.ac.jp.Molecular Pharmacology, Department of Biofunctional Evaluation, Gifu Pharmaceutical University, Gifu, Japan; Department of Biomedical Research Laboratory, Gifu Pharmaceutical University, Gifu, Japan. Electronic address: hidehara@gifu-pu.ac.jp.

Pub Type(s)

Journal Article

Language

eng

PubMed ID

32217192

Citation

Saito, Yuichi, et al. "A Triterpenoid Nrf2 Activator, RS9, Promotes LC3-associated Phagocytosis of Photoreceptor Outer Segments in a P62-independent Manner." Free Radical Biology & Medicine, vol. 152, 2020, pp. 235-247.
Saito Y, Yako T, Otsu W, et al. A triterpenoid Nrf2 activator, RS9, promotes LC3-associated phagocytosis of photoreceptor outer segments in a p62-independent manner. Free Radic Biol Med. 2020;152:235-247.
Saito, Y., Yako, T., Otsu, W., Nakamura, S., Inoue, Y., Muramatsu, A., Nakagami, Y., Shimazawa, M., & Hara, H. (2020). A triterpenoid Nrf2 activator, RS9, promotes LC3-associated phagocytosis of photoreceptor outer segments in a p62-independent manner. Free Radical Biology & Medicine, 152, 235-247. https://doi.org/10.1016/j.freeradbiomed.2020.03.012
Saito Y, et al. A Triterpenoid Nrf2 Activator, RS9, Promotes LC3-associated Phagocytosis of Photoreceptor Outer Segments in a P62-independent Manner. Free Radic Biol Med. 2020 Mar 23;152:235-247. PubMed PMID: 32217192.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - A triterpenoid Nrf2 activator, RS9, promotes LC3-associated phagocytosis of photoreceptor outer segments in a p62-independent manner. AU - Saito,Yuichi, AU - Yako,Tomohiro, AU - Otsu,Wataru, AU - Nakamura,Shinsuke, AU - Inoue,Yuki, AU - Muramatsu,Aomi, AU - Nakagami,Yasuhiro, AU - Shimazawa,Masamitsu, AU - Hara,Hideaki, Y1 - 2020/03/23/ PY - 2020/02/20/received PY - 2020/03/19/accepted PY - 2020/3/29/pubmed PY - 2020/3/29/medline PY - 2020/3/29/entrez KW - AMP-Activated protein kinase (AMPK) KW - Age-related macular degeneration (AMD) KW - LC3-Associated phagocytosis KW - Nuclear factor erythroid 2-related factor 2 (Nrf2) KW - Retinal pigment epithelium (RPE) KW - p62 SP - 235 EP - 247 JF - Free radical biology & medicine JO - Free Radic. Biol. Med. VL - 152 N2 - Daily phagocytosis of shed photoreceptor outer segments (POS) by the retinal pigment epithelium (RPE) is required to sustain the visual function. Recent reports revealed that POS phagocytosis is progressed with LC3-associated manner. Patients with age-related macular degeneration (AMD) had impaired autophagic degradation in the RPE. Nrf2 is a key antioxidant transcriptional regulator that ameliorates oxidative stress which is another contributor to AMD pathogenesis. Nrf2 activation also induces the autophagy receptor protein, p62. However, the role of the Nrf2-p62 pathway in LC3-associated phagocytosis of POS is poorly understood. Here, we investigated the relationships between Nrf2 activation and POS phagocytosis progression. A triterpenoid Nrf2 activator, RS9, facilitated POS uptake into phagolysosomes in RPE cells. RS9 also induced the expression of the autophagy-related proteins, LC3-II and p62, as well as phase-2 antioxidant enzymes. The effect of RS9 on POS phagocytosis was abolished by autophagy inhibition. Unexpectedly, p62 knockdown did not inhibit the effect of RS9 on POS phagocytosis, although, RS9-mediated LC3-II induction by RS9 was inhibited in p62 knockdown RPE cells. We also found that RS9 activated the AMPKα-mTOR signaling pathway earlier than p62 induction. Knockdown of AMPKα1, but not α2, inhibited the RS9-mediated activation of LC3-associated phagocytosis and RS9-mediated induction of LC3-II. Furthermore, intravitreal treatment of RS9 to adult mice decreased the size of POS phagolysosomes after light exposure. Collectively, these results showed that RS9-mediated activation of POS phagocytosis was mainly ascribed to the enhancement of autophagy via AMPKα1 activation. Our findings reveal novel effects of Nrf2 and AMPK α1 activation that contribute to the maintenance of the RPE function via LC3-associated POS phagocytosis. SN - 1873-4596 UR - https://www.unboundmedicine.com/medline/citation/32217192/A_triterpenoid_Nrf2_activator_RS9_promotes_LC3_associated_phagocytosis_of_photoreceptor_outer_segments_in_a_p62_independent_manner_ L2 - https://linkinghub.elsevier.com/retrieve/pii/S0891-5849(20)30456-1 DB - PRIME DP - Unbound Medicine ER -
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