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

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

  • Commun Biol. 2021 Feb 24;4(1):248. doi: 10.1038/s42003-021-01763-5.
Sayan Ghosh 1,  Haitao Liu  # 1,  Meysam Yazdankhah  # 1,  Nadezda Stepicheva  # 1,  Peng Shang  # 1,  Tanuja Vaidya 2,  Stacey Hose 1,  Urvi Gupta 1,  Michael Joseph Calderon 3,  Ming-Wen Hu 4,  Archana Padmanabhan Nair 2,  Joseph Weiss 1,  Christopher S Fitting 1,  Imran A Bhutto 4,  Santosh Gopi Krishna Gadde 2,  Naveen Kumar Naik 2,  Chaitra Jaydev 2,  Gerard A Lutty 4,  James T Handa 4,  Ashwath Jayagopal 5,  Jiang Qian 4,  José-Alain Sahel 1 6,  Dhivyaa Rajasundaram 7,  Yuri Sergeev 8,  J Samuel Zigler Jr 4,  Swaminathan Sethu 2,  Simon Watkins 3,  Arkasubhra Ghosh 2,  Debasish Sinha 9 10 11
Affiliations

Affiliations

  • 1 Department of Ophthalmology, University of Pittsburgh School of Medicine, Pittsburgh, PA, USA.
  • 2 GROW Research Laboratory, Narayana Nethralaya Foundation, Bengaluru, India.
  • 3 Department of Cell Biology and Center for Biologic Imaging, University of Pittsburgh School of Medicine, Pittsburgh, PA, USA.
  • 4 Wilmer Eye Institute, The Johns Hopkins University School of Medicine, Baltimore, MD, USA.
  • 5 Kodiak Sciences, Palo Alto, CA, USA.
  • 6 Institut de la Vision, INSERM, CNRS, Sorbonne Université, Paris, France.
  • 7 Department of Pediatrics, Children's Hospital of Pittsburgh, University of Pittsburgh School of Medicine, Pittsburgh, PA, USA.
  • 8 National Eye Institute, National Institutes of Health, Bethesda, MD, USA.
  • 9 Department of Ophthalmology, University of Pittsburgh School of Medicine, Pittsburgh, PA, USA. Debasish@pitt.edu.
  • 10 Department of Cell Biology and Center for Biologic Imaging, University of Pittsburgh School of Medicine, Pittsburgh, PA, USA. Debasish@pitt.edu.
  • 11 Wilmer Eye Institute, The Johns Hopkins University School of Medicine, Baltimore, MD, USA. Debasish@pitt.edu.
  • # Contributed equally.
PMID: 33627831 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.

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