Aberrant disulphide bonding contributes to the ER retention of alpha1-antitrypsin deficiency variants

Human Molecular Genetics
Riccardo RonzoniAnna M Fra

Abstract

Mutations in alpha1-antitrypsin (AAT) can cause the protein to polymerise and be retained in the endoplasmic reticulum (ER) of hepatocytes. The ensuing systemic AAT deficiency leads to pulmonary emphysema, while intracellular polymers are toxic and cause chronic liver disease. The severity of this process varies considerably between individuals, suggesting the involvement of mechanistic co-factors and potential for therapeutically beneficial interventions. We show in Hepa1.6 cells that the mildly polymerogenic I (Arg39Cys) AAT mutant forms aberrant inter- and intra-molecular disulphide bonds involving the acquired Cys39 and the only cysteine residue in the wild-type (M) sequence (Cys232). Substitution of Cys39 to serine partially restores secretion, showing that disulphide bonding contributes to the intracellular retention of I AAT. Covalent homodimers mediated by inter-Cys232 bonding alone are also observed in cells expressing the common Z and other polymerising AAT variants where conformational behaviour is abnormal, but not in those expressing M AAT. Prevention of such disulphide linkage through the introduction of the Cys232Ser mutation or by treatment of cells with reducing agents increases Z AAT secretion. Our results rev...Continue Reading

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Citations

Mar 15, 2018·Human Molecular Genetics·Mattia LaffranchiAnnamaria Fra
Feb 15, 2018·Physiological Reviews·Ya-Xiong Tao, P Michael Conn
Jul 20, 2018·The Journal of Biological Chemistry·Lydia LamribenDaniel N Hebert
Sep 23, 2018·The Journal of Biological Chemistry·Eugene SerebryanyEugene I Shakhnovich
Oct 31, 2019·The Journal of Biological Chemistry·Benjamin M AdamsDaniel N Hebert
May 3, 2018·Frontiers in Pharmacology·Sabina JanciauskieneJoanna Chorostowska-Wynimko
Jun 22, 2017·Frontiers in Molecular Neuroscience·Annamaria FraRoberto Sitia
Jul 13, 2018·Orphanet Journal of Rare Diseases·María Torres-DuránFrancisco Dasí
Apr 4, 2021·Journal of Clinical Medicine·María MagallónFrancisco Dasí
Jun 4, 2021·Scientific Reports·Peristera RobotiStephen High
Jun 3, 2021·International Journal of Molecular Sciences·Riccardo RonzoniAnnamaria Fra
Jun 22, 2021·JHEP Reports : Innovation in Hepatology·Esra KaratasMarion Bouchecareilh

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