Keratin 8 (K8) may play an important role in early-stage endoplasmic reticulum-associated degradation (ERAD), a process that has been implicated in the pathogenesis of alpha-1 antitrypsin deficiency (AATD) and cystic fibrosis (CF).
“We provide proof of concept that modulation of K8-containing ERAD complexes increases Z-A1AT [Z-alpha-1 antitrypsin] secretion from HeLa, and patients derived primary human respiratory epithelial (HNE) cells and could be a target for pharmacotherapy in AATD,” said the authors of the study published in bioRxiv.
The authors suggest that K8 is involved in the initiation of retrotranslocation and ubiquitination of the proteins responsible for AATD and CF, ie, Z-A1AT and mutant (F508del) CF transmembrane conductance regulator (CFTR) protein.
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The reduction of K8 concentration increased by 13-fold the secretion of Z-A1AT and by 4-fold the secretion of wild-type A1AT through the conventional secretory pathway. Moreover, it triggered endoplasmic reticulum failure and apoptosis in conditions of endoplasmic reticulum stress.
Mechanistic insights suggest that K8 is recruited to complexes containing major ERAD components, such as derlin-2, ERAD-associated E3 ubiquitin-protein ligase (Hrd1), and Sel-1 protein. The association between K8 and derlin-2 seems to be permanent, while the recruitment of Hrd1 and Sel-1 to the complex seems to be dependent on the expression of misfolded Z-A1AT.
Treating cells with the small molecule c407, already described as a disruptor of the K8/F508del-CFTR interaction, increased the secretion of Z-A1AT in primary differentiated HNE cells derived from patients and Z-A1AT-expressing HeLa cells. However, it failed to increase the secretion of wild-type A1AT.
c407 interfered with the recruitment of K8 and derlin-2 to ERAD complexes, but not with Sel-1 and Hrd1. Therefore, it couldn’t disrupt ERAD complexes completely which would be deleterious for cells and inappropriate to therapy, the authors said. Given the results, they suggest that K8-Derlin2 complexes might be a promising target for pharmacotherapy.
Pranke IM, Chevalier B, Premchandar A, et al. Keratin 8 is a scaffolding and regulatory protein of ERAD complexes. bioRxiv. Published online February 1, 2022. doi:10.1101/2022.02.01.478623