\u03b2A1-crystallin regulates glucose metabolism and mitochondrial function in mouse retinal astrocytes by modulating PTP1B activity

Sayan Ghosh,Naveen Kumar Naik,Archana Padmanabhan Nair,Chaitra Jaydev,Stacey Hose,Santosh Gopi Krishna Gadde,Tanuja Vaidya,Michael Calderon ,Meysam Yazdankhah,Swaminathan Sethu,Gerard A Lutty,Christopher Scott Fitting ,Ashwath Jayagopal,Yuri V Sergeev ,Peng Shang,Haitao Liu,Simon C Watkins ,Urvi Gupta,J Sahel ,Imran Ahmed Bhutto ,Arkasubhra Ghosh,Joseph Weiss,Ming Hu ,Jiang Qian,James T Handa,J Samuel Zigler,Dhivyaa Rajasundaram,Nadezda A Stepicheva ,Debasish Sinha

doi:10.1038/s42003-021-01763-5

Abstract

βA3/A1-crystallin, a lens protein that is also expressed in astrocytes, is produced as βA3 and βA1-crystallin isoforms by leaky ribosomal scanning. In a previous human proteome high-throughput array, we found that βA3/A1-crystallin interacts with protein tyrosine phosphatase 1B (PTP1B), a key regulator of glucose metabolism. This prompted us to explore possible roles of βA3/A1-crystallin in metabolism of retinal astrocytes. We found that βA1-crystallin acts as an uncompetitive inhibitor of PTP1B, but βA3-crystallin does not. Loss of βA1-crystallin in astrocytes triggers metabolic abnormalities and inflammation. In CRISPR/cas9 gene-edited βA1-knockdown (KD) mice, but not in βA3-knockout (KO) mice, the streptozotocin (STZ)-induced diabetic retinopathy (DR)-like phenotype is exacerbated. Here, we have identified βA1-crystallin as a regulator of PTP1B; loss of this regulation may be a new mechanism by which astrocytes contribute to DR. Interestingly, proliferative diabetic retinopathy (PDR) patients showed reduced βA1-crystallin and higher levels of PTP1B in the vitreous humor.

Highlights

ΒA3/A1-crystallin, a lens protein that is expressed in astrocytes, is produced as βA3 and βA1-crystallin isoforms by leaky ribosomal scanning
In a previous human proteome high-throughput array (CDI Laboratories, Inc.), we found that βA3/A1-crystallin interacts with PTP1B4, an enzyme that links metabolism and inflammation in diabetes[5]
In a human proteome high-throughput array we found that βA3/A1-crystallin interacts with PTP1B4, an enzyme that links glucose metabolism and inflammation in diabetes[5]

Summary

Introduction

ΒA3/A1-crystallin, a lens protein that is expressed in astrocytes, is produced as βA3 and βA1-crystallin isoforms by leaky ribosomal scanning. In a previous human proteome highthroughput array, we found that βA3/A1-crystallin interacts with protein tyrosine phosphatase 1B (PTP1B), a key regulator of glucose metabolism. This prompted us to explore possible roles of βA3/A1-crystallin in metabolism of retinal astrocytes. Leaky ribosomal scanning is sometimes used to control the expression of regulatory genes[2,3], and it is possible that Cryba[1] is an important regulatory gene in cells where it does not appear to be a structural protein, such as astrocytes. To determine if the βA1 and βA3 isoforms have distinct functions, we generated βA3-crystallin knockout (βA3 KO) and βA1-crystallin knockdown (βA1 KD)

Methods

Results

Conclusion