Lily Wu
The cellular mechanisms of somatic rescue in a1-antitrypsin associated liver disease
Abstract
Background
Somatic mutations can generate advantageous new gene variants that benefit cell growth in disease. We reported in Nature Genetics (2025) that hepatic nodules in the cirrhotic Pi*ZZ livers are dramatically enriched for heterozygous mutations in SERPINA1 that generate C-terminal truncating mutants of Z-A1AT. We showed that truncation mutants reduced Z-A1AT polymer accumulation in patient livers and rescued the structure of the endoplasmic reticulum of Z-A1AT-expressing cells. Additionally, we observed that C-terminal truncation mutants may incorporate into Z-A1AT polymers to “cap” them from further growth. Our preliminary data suggest that C-terminal somatic mutants accelerate the loss of Z-A1AT from cells. Thus, somatic mutations are selected for in the livers of Pi*ZZ individuals and can dominantly suppress Z-A1AT retention. I wish to identify the mechanisms underpinning the dominant suppression of polymer accumulation through the following specific aims.
Aims
- Determine average Z-A1AT polymer length when expressed with truncating mutants
- Evaluate effects of somatic mutants on synthesis, degradation and secretion of Z-A1AT
- Investigate the interactome of C-terminal somatic mutants
Together, these complementary, yet independent aims will help give us insights into the cellular mechanisms that underpin the reduction of Z polymer accumulation in Pi*ZZ livers by naturally occurring somatic variants and help future design of therapies to promote hepatocyte cell health in A1AT associated liver disease.
This work will be hosted by the lab of Stefan Marciniak (CIMR, University of Cambridge, UK) with Dr Joseph Chambers (CIMR, University of Cambridge, UK), in collaboration with the lab of Dr Ioanna Mela (Department of Pharmacology, University of Cambridge, UK).
Biography
After completing her BSc in Medical Biosciences at Imperial College London, Lily began her PhD at the University of Cambridge in the lab of Professor Stefan Marciniak, under the guidance of Dr Joseph Chambers. She studied the cellular and molecular mechanisms of natural occurring somatic variants in the liver of patients with alpha-1 antitrypsin deficiency in liver disease progression. Her research interests include protein folding, protein quality control and ER biology.