Work

A prion-like domain in Gag capsid protein drives retrotransposon particle assembly and mobility

Year: 2023

Type: article

Abstract: Prion domains are diverse amino acid sequences that acquire alternative conformations that become self-propagating.Transformation of proteins into prions is generally accompanied by a propensity to aggregate proteins into oligomers.Some prion proteins cause fatal neurodegenerative disorders while others can perform cellular functions (1).In this issue of PNAS, Beckwith et al. demonstrate that Ty1, a retroviruslike retrotransposon in budding yeast, encodes a prion-like domain (PrLD) within the capsid protein.The study describes the prionogenic activity of the Ty1 PrLD and its essential roles in virus-like particle (VLP) morphology and assembly and in retrotransposition (2).Retrotransposons propagate in genomes by reverse transcription of an RNA intermediate and integration of the resulting complementary double-strand DNA (cDNA) into a new genomic location.Retrotransposons play a major role in genome evolution.Recent work has shown that intermediate steps in retrotransposon replication can have significant health impacts, regardless of whether cDNA is introduced into the host genome, highlighting the importance of understanding all steps of retrotransposon replication.Cytoplasmic cDNA production from human Alu or L1 retrotransposons triggers innate immune responses contributing to macular degeneration or cell aging, respectively (3, 4).Furthermore, retroviral particles formed by endogenous retroviruses can contribute to senescence and tissue aging (5).Long terminal repeat (LTR)-retrotransposons are structurally and functionally related to retroviruses, collectively known as retroelements, except that LTR-retrotransposons lack an envelope gene and are not infectious.The Ty1 and Ty3 LTRretrotransposons of the yeast Saccharomyces cerevisiae have served as excellent models for retroelement replication and regulation (6, 7).Ty1 has a classic LTR-retrotransposon organization with LTRs flanking GAG and POL open reading frames (Fig. 1).The GAG gene encodes a structural protein with RNAbinding domains that forms VLPs to encapsidate and protect Ty1 RNA.The POL gene encodes the enzymatic activities protease (PR), integrase (IN), and reverse transcriptase ribonuclease H (RT-RH), required for retrotransposition.Cytoplasmic VLPs play an essential role in the replication cycle, keeping Ty1 RNA and the enzymatic activities required for replication in close proximity.They are the sites of RNA packaging, Gag-Pol precursor maturation and reverse transcription of RNA into cDNA.Membraneless cytoplasmic foci, where retrotransposon RNA and proteins are assembled, have been identified for Ty1 and Ty3 and may represent an essential step in VLP formation (8-10).However, it was not understood how these foci, known as retrosomes, transition into mature VLPs.Beckwith et al. characterized the N-terminal portion of Ty1 Gag with the broader goal of learning more about retrosome and VLP formation.No function had previously been

Source: Proceedings of the National Academy of Sciences

DOI: 10.1073/pnas.2311419120

Authors: Pascale Lesage, Patrick H. Maxwell