?A1-crystallin regulates glucose metabolism and mitochondrial function in mouse retinal astrocytes by modulating PTP1B activity.

ABSTRACT: ?A3/A1-crystallin, a lens protein that is also expressed in astrocytes, is produced as ?A3 and ?A1-crystallin isoforms by leaky ribosomal scanning. In a previous human proteome high-throughput array, we found that ?A3/A1-crystallin interacts with protein tyrosine phosphatase 1B (PTP1B), a key regulator of glucose metabolism. This prompted us to explore possible roles of ?A3/A1-crystallin in metabolism of retinal astrocytes. We found that ?A1-crystallin acts as an uncompetitive inhibitor of PTP1B, but ?A3-crystallin does not. Loss of ?A1-crystallin in astrocytes triggers metabolic abnormalities and inflammation. In CRISPR/cas9 gene-edited ?A1-knockdown (KD) mice, but not in ?A3-knockout (KO) mice, the streptozotocin (STZ)-induced diabetic retinopathy (DR)-like phenotype is exacerbated. Here, we have identified ?A1-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 ?A1-crystallin and higher levels of PTP1B in the vitreous humor.

SUBMITTER: Ghosh S 

PROVIDER: S-EPMC7904954 | biostudies-literature | 2021 Feb

REPOSITORIES: biostudies-literature