Predicted Cellular Interactors of the Endogenous Retrovirus-K Integrase Enzyme

Abstract

Integrase (IN) enzymes are found in all retroviruses and are crucial in the retroviral integration process. Many studies have revealed how exogenous IN enzymes, such as the human immunodeficiency virus (HIV) IN, contribute to altered cellular function. However, the same consideration has not been given to viral IN originating from symbionts within our own DNA. Endogenous retrovirus-K (ERVK) is pathologically associated with neurological and inflammatory diseases along with several cancers. The ERVK IN interactome is unknown, and the question of how conserved the ERVK IN protein–protein interaction motifs are as compared to other retroviral integrases is addressed in this paper. The ERVK IN protein sequence was analyzed using the Eukaryotic Linear Motif (ELM) database, and the results are compared to ELMs of other betaretroviral INs and similar eukaryotic INs. A list of putative ERVK IN cellular protein interactors was curated from the ELM list and submitted for STRING analysis to generate an ERVK IN interactome. KEGG analysis was used to identify key pathways potentially influenced by ERVK IN. It was determined that the ERVK IN potentially interacts with cellular proteins involved in the DNA damage response (DDR), cell cycle, immunity, inflammation, cell signaling, selective autophagy, and intracellular trafficking. The most prominent pathway identified was viral carcinogenesis, in addition to select cancers, neurological diseases, and diabetic complications. This potentiates the role of ERVK IN in these pathologies via protein–protein interactions facilitating alterations in key disease pathways.

Predicted cellular interactors of the endogenous retrovirus-K protease enzyme

“…In addition, only ERVK PR contained an Nterminal SxIP motif (Figure 1, aa. 80-94) that binds to EBH domains in end-binding proteins involved in microtubule transport (56), similar to what is predicted for ERVK integrase (57). This pattern of consistent SxIP motifs in ERVK proteins may point to a unique usage of microtubule networks through EBH domain interaction.…”

“…80-94) for binding to EBH domains in end-binding proteins involved in microtubule transport (56). Of note, ERVK IN is also predicted to interact with end-binding proteins (57), and the same SxIP motif (ELME000254) is found in both ERVK enzymes. The cluster related to the plus-end tracking proteins (+TIP) consist of only microtubule associated protein RP/EB family members (MAPRE1, MAPRE2, and MAPRE3) and the microtubule motor protein kinesin family member 14 (KIF14), making it by far the smallest grouping within the ERVK PR interactome (Figure 3).…”

Genetic and Molecular Characterization of the Immortalized Murine Hepatic Stellate Cell Line GRX

“…However, the REEAD analysis performed showed that no viruses with active integrase can be detected in the cell culture supernatant. Integrase enzymes are found in all retroviruses and are highly crucial for the process of viral integration into host DNA and virion maturation [67]. The finding that our MLV-specific integrase probes were unable to detect MLV-integrase in supernatants of cultured GRX cells might indicate that the produced viral particles strongly adhere to the surface of the cells.…”

Exploring HERV-K (HML-2) Influence in Cancer and Prospects for Therapeutic Interventions

“…For example, HERV-K (HML-2) integrase binds to a protein called TRIM28, which is involved in gene silencing and DNA repair. This interaction may help HERV-K (HML-2) evade host defense mechanisms and increase its integration efficiency [137].…”