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SPCS1-Dependent E2-p7 processing determines HCV Assembly efficiency.
Nabeel Alzahrani1, Ming-Jhan Wu1, Carla F Sousa2
1Department of Microbiology and Immunology, University of Texas Medical Branch at Galveston, Galveston, Texas, United States of America.
Plos Pathogens
|February 7, 2022
Summary
Signal peptidase complex subunit 1 (SPCS1) regulates Hepatitis C virus (HCV) assembly by facilitating E2-p7 protein processing. This discovery reveals a common role for SPCS1 in Flaviviridae virus propagation.
Area of Science:
- Virology
- Molecular Biology
- Structural Biology
Background:
- Signal peptidase complex subunit 1 (SPCS1) is a known proviral factor for Flaviviridae viruses.
- SPCS1's role in flavivirus propagation involves regulating signal peptidase complex (SPC)-mediated polyprotein processing, particularly the C-prM junction.
- The specific role of SPCS1 in Hepatitis C virus (HCV) polyprotein processing remained unclear.
Purpose of the Study:
- To investigate whether SPCS1 regulates SPC-mediated processing sites within the HCV polyprotein.
- To determine the mechanism by which SPCS1 influences HCV assembly.
- To establish the conserved function of SPCS1 in Flaviviridae virus propagation.
Main Methods:
- Experimental determination of SPCS1's effect on HCV E2-p7 processing by SPC.
- Assessment of SPCS1's dispensability for HCV assembly when E2-p7 separation is efficient.
- Structural modeling and molecular dynamics (MD) simulations to analyze p7 N-terminal transmembrane helix-1 (p7/TM1/helix-1) structure and membrane interactions.
- Analysis of p7 mutations impacting E2-p7 processing and their effect on SPCS1 function.
Main Results:
- Loss of SPCS1 specifically impairs the SPC-mediated processing of the HCV E2-p7 junction.
- Efficient E2-p7 separation, independent of SPC processing, renders SPCS1 dispensable for HCV assembly.
- Structural modeling indicates that the rigidity of p7/TM1/helix-1 hinders SPC access to the E2-p7 cleavage site.
- SPCS1 facilitates E2-p7 processing by enhancing the presentation of the E2-p7 junction to the SPC active site.
Conclusions:
- SPCS1 regulates HCV assembly by facilitating SPC-mediated processing of the E2-p7 precursor.
- SPCS1's mechanism involves improving the accessibility of the E2-p7 junction to the SPC.
- This study establishes a common role for SPCS1 in Flaviviridae propagation: regulating SPC-mediated processing of specific, suboptimal cleavage sites, including the E2-p7 junction in HCV.
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