Bioinformatic Characterization of ENPEP, the Gene Encoding a Potential Cofactor for SARS-CoV-2 Infection
Antti Arppo, Harlan Barker, Seppo Parkkila.
Abstract
Research on SARS-CoV-2, the viral pathogen that causes COVID-19, has identified angiotensin converting enzyme 2 (ACE2) as the primary viral receptor. Several genes that encode viral cofactors, such as TMPRSS2, NRP1, CTSL, and possibly KIM1, have since been discovered. Glutamyl aminopeptidase (APA), encoded by the gene ENPEP, is another cofactor candidate due to similarities in its biological role and high correlation with ACE2 and other human coronavirus receptors, such as aminopeptidase N (APN) and dipeptidyl peptidase 4 (DPP4). Recent studies have proposed a role for ENPEP as a viral receptor in humans, and ENPEP and ACE2 are both closely involved in the renin-angiotensin-aldosterone system proposed to play an important role in SARS-CoV-2 pathophysiology.
Introduction
The coronavirus disease 2019 (COVID-19) pandemic presented the world with a health crisis thus far unprecedented in the 21st century and prompted extensive research into the molecular mechanisms of the underlying pathogen, SARS-CoV-2. Belonging to the genus Betacoronaviridae, the virus was found to be closely related to the prior SARS-CoV responsible for the SARS epidemic, with evident similarities: both use the same transmembrane enzyme, angiotensin converting enzyme 2 (ACE2), as a viral receptor, a trimeric spike (S) glycoprotein for facilitating viral binding and entry, and the host protease transmembrane serine protease (TMPRSS2) to prime the fusion machinery and achieve cellular entry.
Methods:
Identification of correlated enhancer RNAs (eRNAs) was performed using custom Python scripts utilizing data from the HeRA database. eRNAs with a strong correlation (≥0.60) with the ENPEP gene in any tissue were identified, and all other genes strongly correlated with the eRNA in the same tissue were also retrieved.
Discussion
Comparing our results with our previous study on the distribution and characteristics of ACE2, it appears that ENPEP and ACE2 are involved in very similar biological processes, sharing 4 out of the top 5 biological process ontologies: blood vessel morphogenesis, blood vessel development, vasculature development and cardiovascular system development. Notably, angiogenesis is the process most strongly correlated with ENPEP rather than its classically known role in the degradation of ANG2 in the RAAS. Furthermore, NRP1, the gene with the highest overall correlation to ENPEP, is also intimately involved in vascular development, functioning as a receptor for angiogenic peptides such as VEGF165 and SEMA3A and possibly promoting blood vessel permeability.
Citation: Arppo A, Barker H, Parkkila S (2024) Bioinformatic characterization of ENPEP, the gene encoding a potential cofactor for SARS-CoV-2 infection. PLoS ONE 19(12): e0307731. https://doi.org/10.1371/journal.pone.0307731
Editor: Cheorl-Ho Kim, Sungkyunkwan University - Suwon Campus: Sungkyunkwan University - Natural Sciences Campus, REPUBLIC OF KOREA
Received: July 10, 2024; Accepted: November 21, 2024; Published: December 11, 2024.
Copyright: © 2024 Arppo et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.
Data Availability: All relevant data are within the manuscript and its Supporting Information files.
Funding: SP received funding from Academy of Finland and Jane and Aatos Erkko Foundation. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.
Competing interests: The authors have declared that no competing interests exist.
