βA1-crystallin regulates glucose metabolism and mitochondrial function in mouse retinal astrocytes by modulating PTP1B activity.

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.

Citation

Sayan Ghosh, Haitao Liu, Meysam Yazdankhah, Nadezda Stepicheva, Peng Shang, Tanuja Vaidya, Stacey Hose, Urvi Gupta, Michael Joseph Calderon, Ming-Wen Hu, Archana Padmanabhan Nair, Joseph Weiss, Christopher S Fitting, Imran A Bhutto, Santosh Gopi Krishna Gadde, Naveen Kumar Naik, Chaitra Jaydev, Gerard A Lutty, James T Handa, Ashwath Jayagopal, Jiang Qian, José-Alain Sahel, Dhivyaa Rajasundaram, Yuri Sergeev, J Samuel Zigler, Swaminathan Sethu, Simon Watkins, Arkasubhra Ghosh, Debasish Sinha. βA1-crystallin regulates glucose metabolism and mitochondrial function in mouse retinal astrocytes by modulating PTP1B activity. Communications biology. 2021 Feb 24;4(1):248

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PMID: 33627831

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