beta-arrestin & ndash;dependent PI(4,5)P-2 synthesis boosts GPCR endocytosis

Jung, Seung-Ryoung1,2,3; Jiang, Yifei2; Seo, Jong Bae4,5; Chiu, Daniel T.2,6; Hille, Bertil1; Koh, Duk-Su1

2021-04-27

10.1073/pnas.2011023118

PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA   影响因子和分区

0027-8424

?-arrestins regulate many cellular functions including intracellular signaling and desensitization of G protein?coupled receptors (GPCRs). Previous studies show that ?-arrestin signaling and receptor endocytosis are modulated by the plasma membrane phosphoinositide lipid phosphatidylinositol-(4, 5)-bisphosphate (PI(4,5)P2). We found that ?-arrestin also helped promote synthesis of PI(4,5)P2 and up-regulated GPCR endocytosis. We studied these questions with the Gq-coupled protease-activated receptor 2 (PAR2), which activates phospholipase C, desensitizes quickly, and undergoes extensive endocytosis. Phosphoinositides were monitored and controlled in live cells using lipid-specific fluorescent probes and genetic tools. Applying PAR2 agonist initiated depletion of PI(4,5)P2, which then recovered during rapid receptor desensitization, giving way to endocytosis. This endocytosis could be reduced by various manipulations that depleted phosphoinositides again right after phosphoinositide recovery: PI(4)P, a precusor of PI(4,5)P2, could be depleted at either the Golgi or the plasma membrane (PM) using a recruitable lipid 4-phosphatase enzyme and PI(4,5)P2 could be depleted at the PM using a recruitable 5-phosphatase. Endocytosis required the phosphoinositides. Knock-down of ?-arrestin revealed that endogenous ?-arrestin normally doubles the rate of PIP5-kinase (PIP5K) after PAR2 desensitization, boosting PI(4,5)P2-dependent formation of clathrin-coated pits (CCPs) at the PM. Desensitized PAR2 receptors were swiftly immobilized when they encountered CCPs, showing a dwell time of ?90 s, 100 times longer than for unactivated receptors. PAR2/ ?-arrestin complexes eventually accumulated around the edges or across the surface of CCPs promoting transient binding of PIP5K-I7. Taken together, ?-arrestins can coordinate potentiation of PIP5K activity at CCPs to induce local PI(4,5)P2 generation that promotes recruitment of PI(4,5)P2-dependent endocytic machinery.

? phosphoinositide lipids GPCR endocytosis PIP5K

SCI

英语

NI期刊

通讯

National Research Foundation of Korea (NRF) grant - Korea government (MSIT)[NRF-2019R1A2C1005719] ; NIH["R01-MH113333","R01-DK080840","R01-GM083913","R37-NS08174"]

Science & Technology - Other Topics

Multidisciplinary Sciences

WOS:000645031000012

NATL ACAD SCIENCES

BIOLOGY & BIOCHEMISTRY;CLINICAL MEDICINE;MULTIDISCIPLINARY;PLANT & ANIMAL SCIENCE;ENVIRONMENT/ECOLOGY;SOCIAL SCIENCES, GENERAL;MICROBIOLOGY;ECONOMICS BUSINESS;IMMUNOLOGY;MATERIALS SCIENCE;MATHEMATICS;SPACE SCIENCE;MOLECULAR BIOLOGY & GENETICS;PHARMACOLOGY & TOXICOLOGY;CHEMISTRY;PSYCHIATRY/PSYCHOLOGY;NEUROSCIENCE & BEHAVIOR;PHYSICS;GEOSCIENCES;AGRICULTURAL SCIENCES;ENGINEERING

Web of Science

1.Univ Washington, Dept Physiol & Biophys, Seattle, WA 98195 USA
2.Univ Washington, Dept Chem, Seattle, WA 98195 USA
3.Southern Univ Sci & Technol, Dept Biomed Engn, Shenzhen 518055, Guangdong, Peoples R China
4.Mokpo Natl Univ, Dept Biosci, Jeonnam 58554, South Korea
5.Mokpo Natl Univ, Dept Biomed Hlth & Life Convergence Sci, Jeonnam 58554, South Korea
6.Univ Washington, Dept Bioengn, Seattle, WA 98195 USA

Jung, Seung-Ryoung,Jiang, Yifei,Seo, Jong Bae,et al. beta-arrestin & ndash;dependent PI(4,5)P-2 synthesis boosts GPCR endocytosis[J]. PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA,2021,118(17).

Jung, Seung-Ryoung,Jiang, Yifei,Seo, Jong Bae,Chiu, Daniel T.,Hille, Bertil,&Koh, Duk-Su.(2021).beta-arrestin & ndash;dependent PI(4,5)P-2 synthesis boosts GPCR endocytosis.PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA,118(17).

Jung, Seung-Ryoung,et al."beta-arrestin & ndash;dependent PI(4,5)P-2 synthesis boosts GPCR endocytosis".PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA 118.17(2021).