Protein disulfide-isomerase A6 (PDIA6) (PDIA6)

Protein disulfide-isomerase A6 (PDIA6), commonly referred to as ERp5, is an endoplasmic reticulum-resident enzyme and molecular chaperone essential for protein quality control [UniProt, 2024]. It catalyzes the formation, reduction, and isomerization of disulfide bonds, ensuring the proper folding of nascent polypeptides and preventing the aggregation of misfolded proteins [PubMed, 2021]. PDIA6 is a key regulator of the unfolded protein response (UPR), specifically modulating the activity of the ER stress sensor IRE1α to maintain cellular homeostasis [NIH, 2014]. In oncology, PDIA6 is frequently upregulated and serves as a prognostic biomarker for poor outcomes in cancers such as pancreatic, lung, and ovarian cancer, where it facilitates tumor growth, immune evasion via MICA shedding, and chemoresistance [Oncotarget, 2016; PubMed, 2021]. Beyond cancer, PDIA6 has been implicated in neurodegenerative diseases and provides a protective effect against ischemia-induced cell death in the heart [NIH, 2012]. Although no specific inhibitors are currently approved, pan-PDI inhibitors like E64FC26 are being explored for their potential to induce lethal ER stress in malignant cells [Frontiers in Oncology, 2021]. Therapeutic targeting of PDIA6 must consider its vital physiological roles, as inhibition may lead to safety concerns such as impaired ciliogenesis or increased sensitivity to ferroptosis in the kidneys [BMB Reports, 2024].

Other names

Endoplasmic reticulum protein 5ER protein 5ERp5Protein disulfide isomerase P5Thioredoxin domain-containing protein 7TXNDC7P5

Inhibition of protein disulfide isomerase enzymatic activity and chaperone function, leading to the accumulation of misfolded proteins, induction of prolonged endoplasmic reticulum stress, and activation of apoptotic pathways [Frontiers in Oncology, 2021].