A multinational team of researchers identified keratin 8 (K8) as a negative regulator of misfolded Z-alpha-1 antitrypsin (Z-AAT) secretory trafficking and proposed a new potential therapeutic strategy for alpha-1 antitrypsin deficiency (AATD).
“Our therapeutical strategy, based on modulation of K8-regulated early [endoplasmic reticulum-associated protein degradation (ERAD)] complexes with chemical compounds opens new perspectives for [AATD] and other epithelial protein misfolded diseases,” the authors wrote in Cellular and Molecular Life Sciences.
The study conducted by Pranke et al showed that treating cells with c407, a small molecule capable of disrupting K8 interactions, increased the secretion of Z-AAT, but not wild-type (wt) AAT. c407 targeted the interaction between K8 and derlin-2 in ERAD complexes. Previous studies have shown that c407 can also target the interaction between K8 and the mutant cystic fibrosis transmembrane conductance regulator, F508del-CFTR, responsible for cystic fibrosis.
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Importantly, c407 did not disrupt the entire ERAD complex, an event that would be toxic for cells and thus inappropriate for therapeutic purposes, as it did not change the interaction between the E3 ligase Hrd1 and its partner Sel1. Also, previous studies suggested that long-term administration of c407 is not toxic to mice.
The study also showed that downregulation of K8 enhanced Z-AAT and wt-AAT secretion, led to endoplasmic reticulum failure, and promoted apoptosis of cells expressing the heavy chain μs subunit of secretory IgM.
Regarding the underlying molecular mechanism, the researchers proposed that K8 may act as a scaffolding platform for early-stage ERAD complexes, modulating Hrd1-dependent ubiquitination and initiation of retrotranslocation.
They showed that K8 was recruited to ERAD complexes, where it interacts with derlin-2 in a relatively permanent way. Moreover, it may facilitate the recruitment of Hrd1 and Sel1 to high-order complexes under the expression of Z-AAT.
Reference
Pranke IM, Chevalier B, Premchandar A, et al. Keratin 8 is a scaffolding and regulatory protein of ERAD complexes. Cell Mol Life Sci. 2022;79(9):503. doi:10.1007/s00018-022-04528-3
