The highly infective coronavirus disease 19 (COVID-19) is caused by a novel strain of coronaviruses – the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) – discovered in December 2019 in the city of Wuhan (Hubei Province, China). Remarkably, COVID-19 has rapidly spread across all continents and turned into a public health emergency, which was ultimately declared as a pandemic by the World Health Organization (WHO) in early 2020. SARS-CoV-2 presents similar aspects to other members of the coronavirus family, mainly regarding its genome, protein structure and intracellular mechanisms, that may translate into mild (or even asymptomatic) to severe infectious conditions. Although the mechanistic features underlying the COVID-19 progression have not been fully clarified, current evidence have suggested that SARS-CoV-2 may primarily behave as other β-coronavirus members. To better understand the development and transmission of COVID-19, unveiling the signaling pathways that may be impacted by SARS-CoV-2 infection, at the molecular and cellular levels, is of crucial importance. In this review, we present the main aspects related to the origin, classification, etiology and clinical impact of SARS-CoV-2. Specifically, here we describe the potential mechanisms of cellular interaction and signaling pathways, elicited by functional receptors, in major targeted tissues/organs from the respiratory, gastrointestinal (GI), cardiovascular, renal, and nervous systems. Furthermore, the potential involvement of these signaling pathways in evoking the onset and progression of COVID-19 symptoms in these organ systems are presently discussed. A brief description of future perspectives related to potential COVID-19 treatments is also highlighted.

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Alterations in the p14ARF tumor suppressor are frequent in many human cancers and are associated with susceptibility to melanoma, pancreatic cancer, and nervous system tumors. In addition to its p53-regulatory functions, p14 ARF has been shown to influence ribosome biogenesis and to regulate the endoribonuclease B23, but there remains considerable controversy about its nucleolar role. We sought to clarify the activities of p14 ARF by studying its interaction with ribosomes. We show that p14 ARF and B23 interact within the nucleolar 60 S preribosomal particle and that this interaction does not require rRNA. In contrast to previous reports, we found that expression of p14 ARF does not significantly alter ribosome biogenesis but inhibits polysome formation and protein translation in vivo. These results suggest a ribosome-dependent p14 ARF pathway that regulates cell growth and thus complements p53-dependent p14 ARF functions.The INK4a/ARF locus on chromosome 9 is frequently altered in human cancer, and inherited INK4a/ARF mutations are associated with melanoma susceptibility in 20 -40% of multiple case melanoma families (1). This complex sequence encodes the melanoma tumor suppressor proteins, p16 INK4a and p14ARF from alternative spliced transcripts in different reading frames (2, 3). Both proteins are centrally involved in the regulation of cell cycle and apoptotic programs in response to oncogenic stimuli and are therefore frequently targeted in tumor development and progression (4). INK4a/ARF-deficient mice are tumor-prone (5-7), and those with melanocyte-specific expression of activated H-ras develop cutaneous melanomas with high penetrance (8). High density mapping on chromosome 9p in human melanomas has identified p14 ARF as the most commonly deleted INK4a/ARF gene (9), and individuals with altered ARF, but apparently wild type p16INK4a , are melanoma-prone (10 -13). p14 ARF interacts with the p53 negative regulator hdm2, and inhibits its p53-specific E3 3 ubiquitin ligase activity (14 -17). It has been proposed that ARF physically sequesters hdm2 in nucleoli, thus relieving nucleoplasmic p53 from hdm2-mediated degradation (18). Recent data, however, suggest that nucleolar relocalization of hdm2 is not required for p53 activation (19) and that the redistribution of ARF into the nucleoplasm enhances its interaction with hdm2 and its p53-dependent growth-suppressive activity (20, 21). Accordingly, increasing nucleolar localization of ARF reduces ARF p53-dependent functions and diminishes ARF-hdm2 complex formation (21). This current model of ARF function supports the concept that nucleolar disruption contributes to p53 signaling (22) because many stress signals perturb the nucleolus, causing the release of nucleolar proteins (including ARF, L11, L23, L5, and B23) that activate the p53 pathway (23-27).Nucleolar ARF, rather than residing in inactive "storage" (20, 21, 28), may regulate ribosome biogenesis by retarding the processing of early 47 S/45 S and 32 S rRNA precursors (29). These effects do not depend on...