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CHOP-c-JUN complex plays a critical role in liver proteotoxicity induced by mutant Z alpha-1 antitrypsin.

Attanasio, S.; Gernoux, G.; Ferriero, R.; De Cegli, R.; Carissimo, A.; Nusco, E.; Campione, S.; Teckman, J.; Piccolo, P.; Brunetti-Pierri, N.

2020-05-05 genetics
10.1101/2020.05.04.076752 bioRxiv
Show abstract

Alpha-1 antitrypsin (AAT) deficiency is a common genetic disorder with lung and liver involvement. Most patients carry the Z allele in SERPINA1 that encodes a mutant AAT (ATZ) forming hepatotoxic polymers. We found CHOP upregulation and activation in both mouse (PiZ) and human livers expressing ATZ. Compared to controls, juvenile PiZ/Chop-/- mice showed reduction in hepatic ATZ and transcriptional response to endoplasmic reticulum stress, as consequence of CHOP-mediated increase of SERPINA1 transcription. CHOP was found to upregulate SERPINA1 though binding with c-JUN on SERPINA1 regulatory elements, thus aggravating hepatic accumulation of ATZ. Increased CHOP levels were detected in diseased livers of children homozygous for the Z allele. Compared to adults, AAT deficiency in infants has different severity and prognosis. Based on our findings, CHOP-c-JUN complex upregulates SERPINA1 transcription and play an important role in the hepatic disease pathogenesis by increasing the burden of proteotoxic ATZ, particularly in the pediatric population.

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