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

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

Automated summary

Ghosh et al. discovered that the lens protein beta A1-crystallin interacts with PTP1B, regulating the metabolism of retinal astrocytes. Knockdown of beta A1-crystallin exacerbates the streptozotocin-induced diabetic retinopathy-like phenotype in mice, indicating a potential target for treating diabetic retinopathy.