Emerging roles of the Protein Phosphatase 1 (PP1) in the context of viral infections

Cell Communication and Signaling Corda et al. Cell Communication and Signaling (2024) 22:65 https://doi.org/10.1186/s12964-023-01468-8 Open Access REVIEW Emerging roles of the Protein Phosphatase 1 (PP1) in the context of viral infections Pedro O. Corda1, Mathieu Bollen2, Daniela Ribeiro1*† and Margarida Fardilha1*† Abstract Protein Phosphatase 1 (PP1) is a major serine/threonine phosphatase in eukaryotes, participating in several cellular processes and metabolic pathways. Due to their low substrate specificity, PP1’s catalytic subunits do not exist as free entities but instead bind to Regulatory Interactors of Protein Phosphatase One (RIPPO), which regulate PP1’s substrate specificity and subcellular localization. Most RIPPOs bind to PP1 through combinations of short linear motifs (4–12 residues), forming highly specific PP1 holoenzymes. These PP1-binding motifs may, hence, represent attractive targets for the development of specific drugs that interfere with a subset of PP1 holoenzymes. Several viruses exploit the host cell protein (de)phosphorylation machinery to ensure efficient virus particle formation and propagation. While the role of many host cell kinases in viral life cycles has been extensively studied, the targeting of phosphatases by viral proteins has been studied in less detail. Here, we compile and review what is known concerning the role of PP1 in the context of viral infections and discuss how it may constitute a putative host-based target for the development of novel antiviral strategies. Keywords Protein Phosphatase 1 (PP1), Viral infections, Virus-host interactions, Host-based target, Antiviral response Introduction Viruses are completely dependent on the host cell machinery [1] and manipulate diverse physiologic and metabolic host pathways to favour infection and ensure the proper formation of new infectious viral particles. Numerous studies have reported that protein phosphorylation is crucial for several steps of the life cycle of different viruses and that specific host protein kinases are hijacked by viruses to promote infection [2–4]. In fact, † Daniela Ribeiro and Margarida Fardilha have equal senior authorship. *Correspondence: Daniela Ribeiro Margarida Fardilha 1 Institute of Biomedicine (iBiMED), Department of Medical Sciences, University of Aveiro, Aveiro, Portugal 2 Department of Cellular and Molecular Medicine, Laboratory of Biosignaling & Therapeutics, Katholieke Universiteit Leuven, Louvain, Belgium these proteins have been pinpointed as potential hostdirected targets for the development of antiviral therapeutics (reviewed by García-Cárceles et al. [2]). While the role of host kinases has been extensively studied in the last decades, the role of host phosphatases in the context of viral infections is still poorly understood. Protein phosphatase 1 (PP1), a member of the phosphoprotein phosphatase (PPP) family, catalyses an important fraction of protein Ser/Thr dephosphorylation events in eukaryotic cells [5]. This phosphatase is involved in the regulation of several cellular processes such as the cell cycle, transcription, protein synthesis, and apoptosis [6– 9]. In mammalian cells, the PP1 catalytic subunit (PP1c) is encoded by three distinct genes that encode three isoforms—PP1α, PP1β/δ, and PP1γ – which are ubiquitously expressed in all tissues [10]. The PP1c isoforms have a nearly identical catalytic core (~ 90%) and mainly differ in their amino (N)- and carboxy (C)- terminal extremities [7]. All PP1c isoforms have poor subtract specificity, hence, no free PP1c pools are expected to exist in cells, to prevent uncontrolled and aberrant dephosphorylation © The Author(s) 2024. Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence, visit http://creativecommons.org/licenses/by/4.0/. The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated in a credit line to the data. Corda et al. Cell Communication and Signaling (2024) 22:65 events [11]. However, PP1 counteracts the activity of over 100 kinases, which is explained by the interaction with regulatory subunits, known as Regulatory Interactors of Protein Phosphatase One (RIPPO), that tightly control the substrate selectivity, localization, and activity of PP1c [6–8, 11, 12]. Currently, about 200 structurally unrelated vertebrate RIPPOs are known [13], enabling cells to generate a huge diversity of functionally distinct PP1 holoenzymes. Most RIPPOs have short linear motifs (SliMs) that mediate binding to PP1. The most common PP1-binding SLiMs are the so-called RVxF, SILK, MyPhoNE, and ΦΦ motifs [14, 15] that dock to surface grooves on the globular catalytic core of PP1c [12, 14, 16]. In addition, some RIPPOs interact with isoform-specific residues in the N- or C-termini of PP1c, accounting for their fairly selective binding to one PP1 isoform [7, 17, 18]. Most RIPPOs have multiple PP1-binding motifs that, together, create a high-affinity interaction interface with PP1c [14]. In recent years, some studies have reported that different viruses are able to hijack PP1 and subvert its activity to favour infection. Here, we review the current knowledge on the role of PP1 within different viruses’ life cycles, discuss its importance for the antiviral immune response, and suggest PP1 and its related mechanisms as potential host-based targets for the development of new antiviral therapies. PP1 in viral infections PP1 promotes Tat‑induced transcription in human immunodeficiency virus infection The human immunodeficiency virus (HIV) is an enveloped retrovirus from the Retroviridae family and its genome is composed of two copies of positive-sense single-stranded RNA. It is classified into two subtypes (HIV-1 and HIV-2), of which HIV-1 is the most prevalent and pathogenic [19]. Among HIV-1 encoded proteins, Tat is a potent transactivator expressed early in infection and has a crucial role in transcriptional activity increment. Tat promotes transcription initiation through interactions with Sp1 elements in the HIV-1 promotor [20], and transcriptional elongation through the recruitment of the host positive transcriptional elongation fa (...truncated)