1. Academic Validation
  2. 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.
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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