Uncovering potential host proteins and pathways that may interact with eukaryotic short linear motifs in viral proteins of MERS, SARS and SARS2 coronaviruses that infect humans

Abstract

A coronavirus pandemic caused by a novel coronavirus (SARS-CoV-2) has spread rapidly worldwide since December 2019. Improved understanding and new strategies to cope with novel coronaviruses are urgently needed. Viruses (especially RNA viruses) encode a limited number and size (length of polypeptide chain) of viral proteins and must interact with the host cell components to control (hijack) the host cell machinery. To achieve this goal, the extensive mimicry of SLiMs in host proteins provides an effective strategy. However, little is known regarding SLiMs in coronavirus proteins and their potential targets in host cells. The objective of this study is to uncover SLiMs in coronavirus proteins that are present within host cells. These SLiMs have a high possibility of interacting with host intracellular proteins and hijacking the host cell machinery for virus replication and dissemination. In total, 1,479 SLiM hits were identified in the 16 proteins of 590 coronaviruses infecting humans. Overall, 106 host proteins were identified that may interact with SLiMs in 16 coronavirus proteins. These SLiM-interacting proteins are composed of many intracellular key regulators, such as receptors, transcription factors and kinases, and may have important contributions to virus replication, immune evasion and viral pathogenesis. A total of 209 pathways containing proteins that may interact with SLiMs in coronavirus proteins were identified. This study uncovers potential mechanisms by which coronaviruses hijack the host cell machinery. These results provide potential therapeutic targets for viral infections.

Fig 1. The data analysis procedures of this study.

Blue words indicate input data. Brown words indicate the results of each step.

Fig 2. SLiM compositions and phylogenetic analysis of orf1ab-encoding proteins and capsid proteins of coronaviruses.

(A) A total of 1,365 SLiMs were identified in 15 viral proteins encoded by orf1ab (nsp1-nsp10 and nsp12-nsp16). (B) A total of 114 SLiMs were identified in capsid proteins. Complete lists of SLiMs in (A) and (B) are shown in S2 Table. (C) Phylogenetic tree of representative orf1ab-encoding proteins. (D) Phylogenetic tree of representative capsid proteins. The number of tree branches that occurred in 1,000 bootstrap replicates are indicated at the branch point.

Fig 3. Venn diagram of number of human proteins interacting with coronavirus proteins mediated by SLiMs.

(A) common and different SLiM interacting proteins between different human coronavirus groups. (B) common and different SLiM interacting proteins among SARS-CoV, SARS-CoV-2 and MERS-CoV.

Fig 4. Venn diagram of the number of target human pathway coronavirus proteins mediated by SLiMs.

(A) Common and different SLiM target pathways between different viral groups. (B) Common and different SLiM target pathways among SARS-CoV, SARS-CoV-2 and MERS-CoV.

Fig 5. Categories (based on the KEGG pathway database) and numbers of pathways that may be affected by coronavirus proteins.

Two hundred and nine pathways contain proteins that interact with 1,479 SLiMs identified in 16 coronavirus proteins (nsp1-nsp10, nsp12-nsp16 and capsid proteins).