Molecular aspects of cytoprotection by Optineurin during stress and disease.

Optineurin/OPTN is an adapter protein that plays a crucial role in mediating many cellular functions, including autophagy, vesicle trafficking, and various signalling pathways. Mutations of OPTN are linked with neurodegenerative disorders, glaucoma, and amyotrophic lateral sclerosis (ALS). Recent work has shown that OPTN provides cytoprotection from many types of stress, including oxidative stress, endoplasmic reticulum stress, protein homeostasis stress, tumour necrosis factor α, and microbial infection.

A glaucoma- and ALS-associated mutant of OPTN induces neuronal cell death dependent on Tbk1 activity, autophagy and ER stress.

Mutations in OPTN are associated with glaucoma, an eye disease, and also with amyotrophic lateral sclerosis (ALS), a motor neuron disease. A 2-bp insertion in OPTN (691_692insAG or 2bpIns-OPTN) is associated with both glaucoma and ALS. This mutation results in frame shift after 127 amino acids, giving rise to a protein with C-terminal aberrant sequence.

Insulin treatment promotes tyrosine phosphorylation of PKR and inhibits polyIC induced PKR threonine phosphorylation.

Tyrosine phosphorylation of insulin receptor beta (IRβ) in insulin treated HepG2 cells is inversely correlated to ser(51) phosphorylation in the alpha-subunit of eukaryotic initiation factor 2 (eIF2α) that regulates protein synthesis. Insulin stimulates interaction between IRβ and PKR, double stranded RNA-dependent protein kinase, also known as EIF2AK2, and phosphorylation of tyrosine residues in PKR, as analyzed by immunoprecipitation and pull down assays using anti-IRβ and anti-phosphotyrosine antibodies, recombinant IRβ and immunopurified PKR. Further polyIC or synthetic double stranded RNA-induced threonine phosphorylation or activation of immunopurified and cellular PKR is suppressed in the presence of insulin treated purified IRβ and cell extracts.