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Nat. Cell Biol., 2022 Dec;24(12):1739-1753 | https://doi.org/10.1038/s41556-022-01031-6 Adherens junctions organize size-selective proteolytic hotspots critical for Notch signalling

Minsuk Kwak^{1,2,3,4,5,6,18}, Kaden M. Southard^1,2,18, Woon Ryoung Kim^1,2,3,18, Annie Lin1,2,3, Nam Hyeong Kim^1,2,3,6,7,8, Ramu Gopalappa^4,9, Hyun Jung Lee^1,2,3, Minji An^4,5, Seo Hyun Choi^4,5, Yunmin Jung^4,5, Kunwoo Noh^4,5, Justin Farlow², Anastasios Georgakopoulos¹⁰, Nikolaos K. Robakis¹⁰, Min K. Kang¹¹, Matthew L. Kutys¹², Daeha Seo¹³, Hyongbum Henry Kim^4,5,9,14,15, Yong Ho Kim^6,7,8, Jinwoo Cheon^4,5,16, Zev J. Gartner^2,17 & Young-wook Jun^1,2,3,4,5

¹Department of Otolaryngology, University of California, San Francisco, CA, USA.
²Department of Pharmaceutical Chemistry, University of California, San Francisco, CA, USA.
³Helen Diller Family Cancer Comprehensive Center (HDFCCC), University of California, San Francisco, CA, USA.
⁴Center for Nanomedicine, Institute for Basic Science (IBS), Seoul, Republic of Korea.
⁵Graduate Program of Nano Biomedical Engineering (Nano BME), Advanced Science Institute, Yonsei University, Seoul, Republic of Korea.
⁶SKKU Advanced Institute of Nanotechnology (SAINT), Sungkyunkwan University, Suwon, Republic of Korea.
⁷Department of Nano Engineering, Sungkyunkwan University, Suwon, Republic of Korea.
⁸Imnewrun Inc., Suwon, Republic of Korea.
⁹Department of Pharmacology, Yonsei University College of Medicine, Seoul, Republic of Korea.
¹⁰Department of Psychiatry and Neuroscience, Icahn School of Medicine at Mount Sinai, New York, NY, USA.
¹¹Department of Neurology, University of California, San Francisco, CA, USA.
¹²Department of Cell and Tissue Biology, University of California, San Francisco, CA, USA.
¹³Department of Physics and Chemistry, DGIST, Daegu, Republic of Korea.
¹⁴Brain Korea 21 Plus Project, Yonsei University College of Medicine, Seoul, Republic of Korea.
¹⁵Severance Biomedical Science Institute, Yonsei University College of Medicine, Seoul, Republic of Korea.
¹⁶Department of Chemistry, Yonsei University, Seoul, Republic of Korea.
¹⁷Chan Zuckerberg Biohub, San Francisco, CA, USA.
¹⁸These authors contributed equally: Minsuk Kwak, Kaden M. Southard, Woon Ryoung Kim

Correspondence and requests for materials should be addressed to Zev J. Gartner or Young-wook Jun

Abstract

Adherens junctions (AJs) create spatially, chemically and mechanically discrete microdomains at cellular interfaces. Here, using a mechanogenetic platform that generates artificial AJs with controlled protein localization, clustering and mechanical loading, we find that AJs also organize proteolytic hotspots for γ-secretase with a spatially regulated substrate selectivity that is critical in the processing of Notch and other transmembrane proteins. Membrane microdomains outside of AJs exclusively organize Notch ligand-receptor engagement (LRE microdomains) to initiate receptor activation. Conversely, membrane microdomains within AJs exclusively serve to coordinate regulated intramembrane proteolysis (RIP microdomains). They do so by concentrating γ-secretase and primed receptors while excluding full-length Notch. AJs induce these functionally distinct microdomains by means of lipid-dependent γ-secretase recruitment and size-dependent protein segregation. By excluding full-length Notch from RIP microdomains, AJs prevent inappropriate enzyme-substrate interactions and suppress spurious Notch activation. Ligand-induced ectodomain shedding eliminates size-dependent segregation, releasing Notch to translocate into AJs for processing by γ-secretase. This mechanism directs radial differentiation of ventricular zone-neural progenitor cells in vivo and more broadly regulates the proteolysis of other large cell-surface receptors such as amyloid precursor protein. These findings suggest an unprecedented role of AJs in creating size-selective spatial switches that choreograph γ-secretase processing of multiple transmembrane proteins regulating development, homeostasis and disease.

논문정보

형식Research article
게재일2022년 12월 (BRIC 등록일 2022-12-12)
연구진국내+국외 연구진
분야 바이오·의료융합 > 바이오센싱 및 나노바이오물질

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