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Host PDZ-containing proteins targeted by SARS-CoV-2.

ABSTRACT: Small linear motifs targeting protein interacting domains called PSD-95/Dlg/ZO-1 (PDZ) have been identified at the C terminus of the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) proteins E, 3a, and N. Using a high-throughput approach of affinity-profiling against the full human PDZome, we identified sixteen human PDZ binders of SARS-CoV-2 proteins E, 3A, and N showing significant interactions with dissociation constants values ranging from 3 to 82 μm. Six of them (TJP1, PTPN13, HTRA1, PARD3, MLLT4, LNX2) are also recognized by SARS-CoV while three (NHERF1, MAST2, RADIL) are specific to SARS-CoV-2 E protein. Most of these SARS-CoV-2 protein partners are involved in cellular junctions/polarity and could be also linked to evasion mechanisms of the immune responses during viral infection. Among the binders of the SARS-CoV-2 proteins E, 3a, or N, seven significantly affect viral replication under knock down gene expression in infected cells. This PDZ profiling identifying human proteins potentially targeted by SARS-CoV-2 can help to understand the multifactorial severity of COVID19 and to conceive effective anti-coronaviral agents for therapeutic purposes.

SUBMITTER: Caillet-Saguy C

PROVIDER: S-EPMC8250131 | biostudies-literature |

REPOSITORIES: biostudies-literature

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Project description:PDZ (Post-synaptic density, PSD-95)/ Disc large, Dlg/ Zonula occludens, ZO-1) proteins are central in the assembly of multiprotein signalling complexes that are formed in distinctive, specialized cell regions. In these complexes different signals are orchestrated and traduced into quick and efficient responses controlling cell polarization and cell communication. Viral pathogens target host PDZ proteins by expressing viral proteins containing a PDZ binding motif (PBM). SARS-CoV-1 and -2 harbour the protein E, a viroporin with a conserved PBM in its carboxyl-terminal region. SARS-CoV-1 E protein is a pathogenicity factor that in epithelia interacts with the PDZ protein PALS1, which promote disruption of cell junctions. SARS-CoV-2 infects epithelia, but also cells from the innate immune response, including monocytes, dendritic cells, and alveolar macrophages. Identification of targets of SARS-CoV-2 E protein in immune cells might offer valuable clues to understand how SARS-CoV-2 alters immune response. Here we generated a SARS-CoV-2 E protein fused to a GFP-tag at the amino terminal. This recombinant protein was used as bait to identify associated proteins in THP-1 cells, a human monocytic cell line that can be differentiated to macrophages and dendritic cells. Analysis of the GFP-E protein interactome provided 372 proteins that fall into different functional groups. Only eight of these proteins harbor PDZ domains, including the cell polarity protein ZO-2 and the chemoattractant IL-16. Syntenin, a PDZ protein previously identified as interactor of SARS-CoV-1 E protein in epithelia, was also found in our analysis. Little is known about these PDZ proteins in immune cells, so we addressed their expression in monocytes and along the differentiation towards macrophages and dendritic cells. Our findings support the notion that viral targeting of PDZ proteins alters inflammatory response and highlight the importance of identifying the functions of PDZ proteins into maintenance of immune fitness.

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Host PDZ-containing proteins targeted by SARS-CoV-2.

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