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Cell Rep. 2018 Oct 23;25(4):833-840.e3. doi: 10.1016/j.celrep.2018.09.088.

NS5A Promotes Constitutive Degradation of IP3R3 to Counteract Apoptosis Induced by Hepatitis C Virus.

Author information

1
Department of Biochemistry and Molecular Pharmacology, Laura and Isaac Perlmutter NYU Cancer Center, New York University School of Medicine, 522 First Avenue, SRB 1107, New York, NY 10016, USA; Howard Hughes Medical Institute, 522 First Avenue, SRB 1107, New York, NY 10016, USA. Electronic address: kuchay@uic.edu.
2
Laboratory of Virology and Infectious Disease, Center for the Study of Hepatitis C, The Rockefeller University, New York, NY 10065, USA.
3
Department of Biochemistry and Molecular Pharmacology, Laura and Isaac Perlmutter NYU Cancer Center, New York University School of Medicine, 522 First Avenue, SRB 1107, New York, NY 10016, USA; Department of Morphology, Surgery and Experimental Medicine, Section of Pathology, Oncology and Experimental Biology, Laboratory for Technologies of Advanced Therapies (LTTA), University of Ferrara, Ferrara, Italy.
4
Department of Biochemistry and Molecular Pharmacology, Laura and Isaac Perlmutter NYU Cancer Center, New York University School of Medicine, 522 First Avenue, SRB 1107, New York, NY 10016, USA.
5
Department of Morphology, Surgery and Experimental Medicine, Section of Pathology, Oncology and Experimental Biology, Laboratory for Technologies of Advanced Therapies (LTTA), University of Ferrara, Ferrara, Italy.
6
Laboratory of Virology and Infectious Disease, Center for the Study of Hepatitis C, The Rockefeller University, New York, NY 10065, USA. Electronic address: ricec@mail.rockefeller.edu.
7
Department of Biochemistry and Molecular Pharmacology, Laura and Isaac Perlmutter NYU Cancer Center, New York University School of Medicine, 522 First Avenue, SRB 1107, New York, NY 10016, USA; Howard Hughes Medical Institute, 522 First Avenue, SRB 1107, New York, NY 10016, USA. Electronic address: michele.pagano@nyumc.org.

Abstract

FBXL2 targets IP3R3 for ubiquitin-mediated degradation to limit Ca2+ flux to mitochondria and, consequently, apoptosis. Efficient replication of hepatitis C virus (HCV) requires geranylgeranylation of FBXL2. Here, we show that the viral protein NS5A forms a trimeric complex with IP3R3 and FBXL2, unmasking IP3R3's degron in the absence of inositol 1,4,5-trisphosphate (IP3) stimulation. FBXL2 knockdown or expression of a stable IP3R3 mutant causes persistent Ca2+ flux and sensitizes cells to apoptosis, resulting in the inhibition of viral replication. Importantly, the effect of FBXL2 silencing is rescued by depleting IP3R3, but not p85β, another established FBXL2 substrate, indicating that the anti-HCV effect of FBXL2 knockdown is largely due to IP3R3 stabilization. Finally, disruption of the FBXL2-NS5A-IP3R3 complex using somatic cell genetics or pharmacologic inhibition results in IP3R3 stabilization and suppression of HCV replication. This study reveals an IP3-independent molecular mechanism through which HCV promotes IP3R3 degradation, thereby inhibiting virus-induced apoptosis and establishing chronic infection.

KEYWORDS:

FBXL2; HCV-NS5A; IP3R3; apoptosis; calcium overload; hepatitis C virus; proteasomal degradation; ubiquitin; ubiquitin ligase

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