TY - JOUR
T1 - βA1-crystallin regulates glucose metabolism and mitochondrial function in mouse retinal astrocytes by modulating PTP1B activity
AU - Ghosh, Sayan
AU - Liu, Haitao
AU - Yazdankhah, Meysam
AU - Stepicheva, Nadezda
AU - Shang, Peng
AU - Vaidya, Tanuja
AU - Hose, Stacey
AU - Gupta, Urvi
AU - Calderon, Michael Joseph
AU - Hu, Ming Wen
AU - Nair, Archana Padmanabhan
AU - Weiss, Joseph
AU - Fitting, Christopher S.
AU - Bhutto, Imran A.
AU - Gadde, Santosh Gopi Krishna
AU - Naik, Naveen Kumar
AU - Jaydev, Chaitra
AU - Lutty, Gerard A.
AU - Handa, James T.
AU - Jayagopal, Ashwath
AU - Qian, Jiang
AU - Sahel, José Alain
AU - Rajasundaram, Dhivyaa
AU - Sergeev, Yuri
AU - Zigler, J. Samuel
AU - Sethu, Swaminathan
AU - Watkins, Simon
AU - Ghosh, Arkasubhra
AU - Sinha, Debasish
N1 - Publisher Copyright:
© 2021, The Author(s).
PY - 2021/12
Y1 - 2021/12
N2 - 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.
AB - 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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U2 - 10.1038/s42003-021-01763-5
DO - 10.1038/s42003-021-01763-5
M3 - Article
C2 - 33627831
AN - SCOPUS:85101591189
SN - 2399-3642
VL - 4
JO - Communications biology
JF - Communications biology
IS - 1
M1 - 248
ER -