Isorhamnetin, a 3'-methoxylated flavonol, enhances the lysosomal proteolysis in J774.1 murine macrophages in a TFEB-independent manner.

Lysosome is the principal organelle for the ultimate degradation of cellular macromolecules, which are delivered through endocytosis, phagocytosis and autophagy. The lysosomal functions have been found to be impaired by fatty foods and aging, and more importantly, the lysosomal dysfunction in macrophages has been reported as a risk of atherosclerosis development. In this study, we searched for dietary polyphenols which possess the activity for enhancing the lysosomal degradation in J774.1, a murine macrophage-like cell line. Screening test utilizing DQ-BSA digestion identified isorhamnetin (3’-O-methylquercetin) as an active compound. Interestingly, structural comparison to inactive flavonols revealed that the chemical structure of the B-ring moiety in isorhamnetin is the primary determinant of its lysosome-enhancing activity. Unexpectedly isorhamnetin failed to inhibit mTORC1-TFEB signaling, a master regulator of lysosomal biogenesis and function. Our data suggested that the other molecular mechanism might be critical for the regulation of lysosomes in macrophages.

内容要旨・審査要旨・論文本文の公開
本論文は，著者Maiko Sakaiの学位論文として提出され，学位審査・授与の対象となっている
This is a pre-copyedited, author-produced version of an article accepted for publication in Bioscience, Biotechnology, and Biochemistry following peer review. The version of record Maiko Sakai, Kohta Ohnishi, Masashi Masuda, Hirokazu Ohminami, Hisami Yamanaka-Okumura, Taichi Hara, Yutaka Taketani, Isorhamnetin, a 3’-methoxylated flavonol, enhances the lysosomal proteolysis in J774.1 murine macrophages in a TFEB-independent manner., Bioscience, Biotechnology, and Biochemistry, Volume 84, Issue 6, 2 June 2020, Pages 1221–1231 is available online at: https://doi.org/10.1080/09168451.2020.1727309