mTOR-dependent loss of PON1 secretion and antiphospholipid autoantibody production underlie autoimmunity-mediated cirrhosis in transaldolase deficiency.
T Winans, Z Oaks, G Choudhary, A Patel, N Huang, T Faludi, D Krakko, J Nolan, J Lewis, Sarah Blair, Z Lai, S K Landas, F Middleton, J M Asara, S K Chung, B Wyman, P Azadi, K Banki, A Perl
Author Information
T Winans: Departments of Medicine, State University of New York, Norton College of Medicine, Syracuse, NY, 13210, USA; Departments of Biochemistry and Molecular Biology, State University of New York, Norton College of Medicine, Syracuse, NY, 13210, USA.
Z Oaks: Departments of Medicine, State University of New York, Norton College of Medicine, Syracuse, NY, 13210, USA; Departments of Biochemistry and Molecular Biology, State University of New York, Norton College of Medicine, Syracuse, NY, 13210, USA.
G Choudhary: Departments of Medicine, State University of New York, Norton College of Medicine, Syracuse, NY, 13210, USA; Departments of Biochemistry and Molecular Biology, State University of New York, Norton College of Medicine, Syracuse, NY, 13210, USA.
A Patel: Departments of Medicine, State University of New York, Norton College of Medicine, Syracuse, NY, 13210, USA; Departments of Biochemistry and Molecular Biology, State University of New York, Norton College of Medicine, Syracuse, NY, 13210, USA.
N Huang: Departments of Medicine, State University of New York, Norton College of Medicine, Syracuse, NY, 13210, USA; Departments of Biochemistry and Molecular Biology, State University of New York, Norton College of Medicine, Syracuse, NY, 13210, USA.
T Faludi: Departments of Medicine, State University of New York, Norton College of Medicine, Syracuse, NY, 13210, USA.
D Krakko: Departments of Medicine, State University of New York, Norton College of Medicine, Syracuse, NY, 13210, USA.
J Nolan: Departments of Medicine, State University of New York, Norton College of Medicine, Syracuse, NY, 13210, USA.
J Lewis: Departments of Medicine, State University of New York, Norton College of Medicine, Syracuse, NY, 13210, USA.
Sarah Blair: Departments of Medicine, State University of New York, Norton College of Medicine, Syracuse, NY, 13210, USA.
Z Lai: Departments of Medicine, State University of New York, Norton College of Medicine, Syracuse, NY, 13210, USA.
S K Landas: Departments of Pathology, State University of New York, Norton College of Medicine, Syracuse, NY, 13210, USA.
F Middleton: Departments of Neuroscience, State University of New York, Norton College of Medicine, Syracuse, NY, 13210, USA.
J M Asara: Division of Signal Transduction, Department of Medicine, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA, USA.
S K Chung: Faculty of Medicine, Macau University of Science and Technology, Taipa, Macau.
B Wyman: Departments of Medicine, State University of New York, Norton College of Medicine, Syracuse, NY, 13210, USA; Departments of Biochemistry and Molecular Biology, State University of New York, Norton College of Medicine, Syracuse, NY, 13210, USA.
P Azadi: University of Georgia, Athens, GA 30602, USA.
K Banki: Departments of Pathology, State University of New York, Norton College of Medicine, Syracuse, NY, 13210, USA.
A Perl: Departments of Medicine, State University of New York, Norton College of Medicine, Syracuse, NY, 13210, USA; Departments of Microbiology and Immunology, State University of New York, Norton College of Medicine, Syracuse, NY, 13210, USA; Departments of Biochemistry and Molecular Biology, State University of New York, Norton College of Medicine, Syracuse, NY, 13210, USA. Electronic address: perla@upstate.edu.
Transaldolase deficiency predisposes to chronic liver disease progressing from cirrhosis to hepatocellular carcinoma (HCC). Transition from cirrhosis to hepatocarcinogenesis depends on mitochondrial oxidative stress, as controlled by cytosolic aldose metabolism through the pentose phosphate pathway (PPP). Progression to HCC is critically dependent on NADPH depletion and polyol buildup by aldose reductase (AR), while this enzyme protects from carbon trapping in the PPP and growth restriction in TAL deficiency. Although AR inactivation blocked susceptibility to hepatocarcinogenesis, it enhanced growth restriction, carbon trapping in the non-oxidative branch of the PPP and failed to reverse the depletion of glucose 6-phosphate (G6P) and liver cirrhosis. Here, we show that inactivation of the TAL-AR axis results in metabolic stress characterized by reduced mitophagy, enhanced overall autophagy, activation of the mechanistic target of rapamycin (mTOR), diminished glycosylation and secretion of paraoxonase 1 (PON1), production of antiphospholipid autoantibodies (aPL), loss of CD161 NK cells, and expansion of CD38 Ito cells, which are responsive to treatment with rapamycin in vivo. The present study thus identifies glycosylation and secretion of PON1 and aPL production as mTOR-dependent regulatory checkpoints of autoimmunity underlying liver cirrhosis in TAL deficiency.
