From the Argonauts Mythological Sailors to the Argonautes RNA-Silencing Navigators: Their Emerging Roles in Human-Cell Pathologies

Abstract

Regulation of gene expression has emerged as a fundamental element of transcript homeostasis. Key effectors in this process are the Argonautes (AGOs), highly specialized RNA-binding proteins (RBPs) that form complexes, such as the RNA-Induced Silencing Complex (RISC). AGOs dictate post-transcriptional gene-silencing by directly loading small RNAs and repressing their mRNA targets through small RNA-sequence complementarity. The four human highly-conserved family-members (AGO1, AGO2, AGO3, and AGO4) demonstrate multi-faceted and versatile roles in transcriptome’s stability, plasticity, and functionality. The post-translational modifications of AGOs in critical amino acid residues, the nucleotide polymorphisms and mutations, and the deregulation of expression and interactions are tightly associated with aberrant activities, which are observed in a wide spectrum of pathologies. Through constantly accumulating information, the AGOs’ fundamental engagement in multiple human diseases has recently emerged. The present review examines new insights into AGO-driven pathology and AGO-deregulation patterns in a variety of diseases such as in viral infections and propagations, autoimmune diseases, cancers, metabolic deficiencies, neuronal disorders, and human infertility. Altogether, AGO seems to be a crucial contributor to pathogenesis and its targeting may serve as a novel and powerful therapeutic tool for the successful management of diverse human diseases in the clinic.

Comparative structural insights and functional analysis for the distinct unbound states of Human AGO proteins

“…Past relevant analyses have emphasized on miRNA loading and the distinction between the bound and unbound states of AGO2, as the structures of AGO3 and AGO4 became recently available. Genomic studies have solidified the distinction of the AGOs in expression under different conditions or tissues, affecting the biological operations of the organism or causing disease 7 . To complement previous findings, we performed molecular dynamics simulations of each AGO unbound state to acquire an insight on their mechanistic details.…”

“…The presence of four members in the human AGO protein family should be explored under a biochemical perspective, extending the existing relevant knowledge from genomics. AGO proteins and their guides have been reported that exhibit a varying profile in expression within the human tissues 7,87,88 . However, each human tissue has its own range of pH values that facilitates the normal operation of the associated biological processes such as membrane transport and normal cellular division.…”

“…The human AGO protein family consists of AGO1, AGO2, AGO3 and AGO4 and each AGO member includes approximately 860 amino acids (aa). Although the AGOs share a high conservation in gene/protein sequence and protein structure, each of them has reported overlapping or distinct functions per biological pathway 7,8 , justifying the existence of the four distinguished members. For instance, AGO2 and AGO3 possess a metal-coordinating catalytic tetrad (DEDH) in their PIWI domain that enables them to perform RNA slicing 9 , whereas AGO1 and AGO4 have not been observed yet to have such a function, although they retain the second catalytic residue ("glutamate finger") and thus playing other subsidiary roles 1,2 .…”

Characteristics of Transfer RNA-Derived Fragments Expressed during Human Renal Cell Development: The Role of Dicer in tRF Biogenesis

“…However, at the present stage of research, it is difficult to determine the role of angiogenin nuclease in cutting the anticodon loop. Angiogenin cleaves C–A and U–A sequences [ 49 , 50 ]. In the analyzed tRNAs, the C–A base pair occurs twice, in tRNAGly(CCC) and tRNAVal(AAC), and in both cases it is cleaved.…”

The Vault Nanoparticle: A Gigantic Ribonucleoprotein Assembly Involved in Diverse Physiological and Pathological Phenomena and an Ideal Nanovector for Drug Delivery and Therapy

“…In particular, it was shown that the 23 nt long variant svRNAb was derived from vtRNA1-1 and that Dicer, a component of the miRNA pathway, was involved in the processing. The authors also demonstrated that svRNAb, similar to miRNAs, could both guide sequence-specific cleavage of a complementary target RNA in vitro and bind to some Argonaute proteins, the core components of the RNA-induced silencing complex (RISC) [ 108 ]. Based on these findings, it was proposed that svRNAb shares mechanisms of gene expression regulation with miRNA.…”