Interaction networks of prion, prionogenic and prion-like proteins in budding yeast, and their role in gene regulation.

Djamel Harbi,Paul M Harrison,Vladimir N Uversky

doi:10.1371/journal.pone.0100615

Abstract

Prions are transmissible, propagating alternative states of proteins. Prions in budding yeast propagate heritable phenotypes and can function in large-scale gene regulation, or in some cases occur as diseases of yeast. Other ‘prionogenic’ proteins are likely prions that have been determined experimentally to form amyloid in vivo, and to have prion-like domains that are able to propagate heritable states. Furthermore, there are over 300 additional ‘prion-like’ yeast proteins that have similar amino-acid composition to prions (primarily a bias for asparagines and glutamines). Here, we examine the protein functional and interaction networks that involve prion, prionogenic and prion-like proteins. Set against a marked overall preference for N/Q-rich prion-like proteins not to interact with each other, we observe a significant tendency of prion/prionogenic proteins to interact with other, N/Q-rich prion-like proteins. This tendency is mostly due to a small number of networks involving the proteins NUP100p, LSM4p and PUB1p. In general, different data analyses of functional and interaction networks converge to indicate a strong linkage of prionogenic and prion-like proteins, to stress-granule assembly and related biological processes. These results further elucidate how prions may impact gene regulation, and reveal a broader horizon for the functional relevance of N/Q-rich prion-like domains.

Highlights

Yeast prions are propagating altered states of proteins that can be transmitted sustainably into yeasts cell during budding, mating or laboratory infection protocols
Evolutionary analysis showed that the [PSI+] prion domain is conserved across fungal clades that diverged more than 1 billion years ago, with only eight other budding yeast proteins showing similar, phylogenetically deep patterns of bias conservation; the [URE3] prion domain is unique to Hemiascomycota, with different parts of it demonstrating purifying selection and frequent N to Q bias switching between clades [11,13]
We looked for Gene Ontology (GO) categories most of whose annotated proteins in yeast appear in the Experimental Prionogenic Domains (EPDs), Experimental Prion Negatives (EPNs) and N/Q-rich Prion-like Proteins (NQPs) sets

Summary

Introduction

Yeast prions are propagating altered states of proteins that can be transmitted sustainably into yeasts cell during budding, mating or laboratory infection protocols. The first well-characterized yeast prions, that underlie the [PSI+] and [URE3] prion states, are propagating amyloid forms of the proteins Sup35p and Ure2p. Tests for in vitro and in vivo amyloid formation were combined with a Sup prion assay, wherein predicted prion-forming domains were fused to the Cterminal part of the Sup35p protein (the protein that underlies the [PSI+] prion), and these constructs tested for the ability to produce [PSI+]-like states in yeast cells [14]. An examination of transcription factor networks containing yeast prions showed that the regulons of three well-characterized prionforming transcription factors Cyc, Mot, and Sfp overlapped at only two genes, one of which was FLO11, a major determinant of multicellularity and cell adhesion [21] They further demonstrated experimentally that the [MOT3+] prion governs the acquisition of multicellularity in budding yeast [21]. Several data analyses converge to indicate a complex networked role for prion/prionogenic and prion-like proteins in stress granule assembly and related processes

Methods

Findings

Conclusions