Secreted LRPAP1 binds and triggers IFNAR1 degradation to facilitate virus evasion from cellular innate immunity.

Secreted LRPAP1 binds and triggers IFNAR1 degradation to facilitate virus evasion from cellular innate immunity.

Publication date: Sep 25, 2023

The crucial role of interferon (IFN) signaling is well known in the restriction or eradication of pathogen invasion. Viruses take a variety of ways to antagonize host defense through eliminating IFN-signaling intracellularly for decades. However, the way by viruses target IFN-signaling extracellularly has not been discovered. Infection by both coronavirus SARS-CoV-2 and enterovirus 71 (EV71 or EV-A71) can cause severe diseases such as neurological disorders and even death in children. Here, we show evidence that the protease of SARS-CoV-2 (3CL) and EV71 (2A) upregulates the expression and secretion of LDL-receptor-related protein-associated protein 1 (LRPAP1). As a ligand, the N-terminus of secreted LRPAP1 binds with the extracellular domain of IFNAR1 that triggers the receptor ubiquitination and degradation and promotes virus infection both in vitro, ex vivo in the mouse brain, and in vivo in newborn mice. A small peptide from the N-terminus of LRPAP1 effectively binds and causes IFNAR1 degradation that enhances both DNA and RNA viral infections, including herpesvirus HSV-1, hepatitis B virus (HBV), EV71, and beta-coronavirus HCoV-OC43; whereas α2M, a LRPAP1 inhibitor, arrests virus infections by stabilizing IFNAR1. Our study demonstrates a new mechanism used by viruses for evading host cell immunity, supporting a strategy for developing pan-antiviral drugs.

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Concepts Keywords
Arrests Binds
Decades Degradation
Herpesvirus Ev71
Mice Host
Stabilizing Ifn


Type Source Name
disease IDO pathogen
disease IDO host
disease MESH Infection
disease MESH neurological disorders
disease MESH death
disease MESH virus infection
disease MESH causes
disease VO Hepatitis B virus
disease VO Enterovirus
disease MESH hepatitis
pathway REACTOME Signal Transduction
disease IDO replication
disease MESH PRRs
drug DRUGBANK Tretinoin
disease IDO innate immune response
disease IDO process
disease VO Flavivirus
disease MESH neurodegenerative diseases
disease VO effective
disease MESH dementias
disease MESH Alzheimer’s disease
disease MESH Atherosclerosis
disease MESH myopia
disease MESH chronic infections
drug DRUGBANK Coenzyme M
disease IDO assay
disease VO injection
disease VO VP4
disease VO dose
disease MESH coronavirus infection
disease VO titer
drug DRUGBANK Proline
disease IDO cell
disease MESH aseptic meningitis
disease MESH encephalitis
disease MESH poliomyelitis
disease MESH mental disorders
drug DRUGBANK Oxygen
disease VO VP1
pathway KEGG Endocytosis
pathway KEGG Lysosome
drug DRUGBANK Methylamine
disease IDO blood
pathway KEGG Viral replication
disease IDO production
disease VO Bacteria
drug DRUGBANK Cholesterol
drug DRUGBANK Isoxaflutole
disease MESH arthritis

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