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
  • 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. [email protected].
  • 10. Department of Cell Biology and Center for Biologic Imaging, University of Pittsburgh School of Medicine, Pittsburgh, PA, USA. [email protected].
  • 11. Wilmer Eye Institute, The Johns Hopkins University School of Medicine, Baltimore, MD, USA. [email protected].
  • # 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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