Hypoxia up-regulated protein 1

HYOU1 (hypoxia up-regulated protein 1) is a 999-amino acid protein that functions as a molecular chaperone in the endoplasmic reticulum, promoting HSPA5/BiP-mediated ATP nucleotide exchange to activate the unfolded protein response during ER stress and hypoxic conditions (UniProt: Q9Y4L1). The protein participates in cytoprotective cellular mechanisms and protein folding processes. Germline mutations in HYOU1 cause immunodeficiency 59 with hypoglycemia (IMD59), an autosomal recessive combined immunodeficiency disorder affecting immune cell development and glucose homeostasis (UniProt: Q9Y4L1).

In Alzheimer's disease, HYOU1 shows disease-relevant dysregulation. Quantitative proteomics analysis of post-mortem AD brain tissue revealed that HYOU1 is significantly down-regulated compared to age-matched controls (mean log2 fold-change −0.48; Chaparral AD proteomics). This reduction in ER stress response capacity may impair the brain's ability to handle proteotoxic misfolding, a hallmark pathological feature of Alzheimer's disease. The down-regulation was detected across the subcellular fractions examined, suggesting a consistent decrease in HYOU1 protein abundance in affected AD brain tissue.