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

Abstract

AbstractβA3/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.

Diabetic retinopathy: Involved cells, biomarkers, and treatments

“…Therefore, βA1-crystallin/PTP1B signaling may regulate inflammatory signaling in astrocytes under hyperglycemic stress. Moreover, βA1-crystallin is the dominant isoform of glucose metabolism in astrocytes and is essential for maintaining mitochondrial function and oxidative stress during HG stress ( Ghosh et al, 2021 ).…”

Reducing Akt2 in retinal pigment epithelial cells causes a compensatory increase in Akt1 and attenuates diabetic retinopathy

“…Many retinal cell types are affected in DR, such as intense loss of inner retinal neurons 9 , dysfunction of Müller cells 10 and astrocytes 11,12 , and activation of microglia 13 . The interaction between inner retinal cells and retinal vascular lesions 14,15 , as well as the influence of photoreceptors (inflammatory signals) 16,17 , retinal ganglion cells (angiogenic factors) 18 , astrocytes (glucose metabolism and mitochondrial function) 12 , and microglia (immune response) 13 on retinal vascular abnormalities in diabetes have been extensively studied.…”