Intein Clustering Suggests Functional Importance in Different Domains of Life

Abstract

Inteins, also called protein introns, are self-splicing mobile elements found in all domains of life. A bioinformatic survey of genomic data highlights a biased distribution of inteins among functional categories of proteins in both bacteria and archaea, with a strong preference for a single network of functions containing replisome proteins. Many nonorthologous, functionally equivalent replicative proteins in bacteria and archaea carry inteins, suggesting a selective retention of inteins in proteins of particular functions across domains of life. Inteins cluster not only in proteins with related roles but also in specific functional units of those proteins, like ATPase domains. This peculiar bias does not fully fit the models describing inteins exclusively as parasitic elements. In such models, evolutionary dynamics of inteins is viewed primarily through their mobility with the intein homing endonuclease (HEN) as the major factor of intein acquisition and loss. Although the HEN is essential for intein invasion and spread in populations, HEN dynamics does not explain the observed biased distribution of inteins among proteins in specific functional categories. We propose that the protein splicing domain of the intein can act as an environmental sensor that adapts to a particular niche and could increase the chance of the intein becoming fixed in a population. We argue that selective retention of some inteins might be beneficial under certain environmental stresses, to act as panic buttons that reversibly inhibit specific networks, consistent with the observed intein distribution.

Impact of a homing intein on recombination frequency and organismal fitness

“…Our findings show that under conditions that include occasional growth of the population, the high fitness cost of the intein guarantees the survival of alleles with the empty target site, even in the absence of inteins without HEN activity. Although here we showed a fitness cost for the intein, several reports have indicated a potential positive role for intein presence, claiming a regulatory function under stress conditions (36)(37)(38)(39)(40). However, our finding that natural H. volcanii populations in the same sampling location tend to be mixed, having both inteinpositive and intein-negative strains sharing the same niche, does not support a strong selective pressure for intein retention in this case.…”

Comparative Genomics of Chrysochromulina Ericina Virus and Other Microalga-Infecting Large DNA Viruses Highlights Their Intricate Evolutionary Relationship with the Established Mimiviridae Family

“…These inteins are inserted in 7 different ORFs: two in the ribonucleotide reductase large subunit (CeV_219), one in a DEAD-like RNA helicase (CeV_416), one in the DNA polymerase (CeV_365), one in an ATP-dependent Lon peptidase (CeV_043), one in an RPB2 paralog (CeV_288), one in a GDP-mannose 4,6-dehydratase (CeV_113), and one at the C terminus of a protein (CeV_451), concatenating an N-terminal U-box domain and a von Willebrand factor (vWA) domain. In general, intein insertions are strongly biased toward DNA-processing enzymes (30,31). Among other explanations (30,31), this bias might result from the fact that viruses are the main vectors of inteins within eukaryotes (32) and that viral metabolisms are mostly limited to DNA processing.…”

“…In general, intein insertions are strongly biased toward DNA-processing enzymes (30,31). Among other explanations (30,31), this bias might result from the fact that viruses are the main vectors of inteins within eukaryotes (32) and that viral metabolisms are mostly limited to DNA processing. In that context, the inteins hosted in a CeV's GDP-mannose 4,6-dehydratase and Lon peptidase are noticeable exceptions, to our knowledge the first such cases reported in eukaryotic viruses.…”

Protein splicing of a recombinase intein induced by ssDNA and DNA damage

“…DNA binding by RadA precursors is also of significance beyond our present study, given our discovery that host proteins may retain some activities prior to splicing. Whether the precursor can form higher-order structures-such as the typical RadA non-DNA-bound heptameric rings (Shin et al 2003) and ssDNA-bound nucleoprotein filaments (Wu et al 2004)-remains an open question that may be relevant to the many intein-containing proteins that form higher-order structures (Novikova et al 2016). Regardless, post-translational protein activation by intein splicing in response to factors pertinent to host protein function, such as substrates or binding partners, represents a new and immediate means for controlling intein-containing protein function in microorganisms.…”

“…Found in approximately one-quarter of bacterial and one-half of archaeal genomes (Novikova et al 2016), inteins have been considered as purely selfish elements (Naor et al 2016). However, 70% of inteins occur in ATP-binding proteins (Novikova et al 2016), and splicing can be regulated by environmental stresses (Callahan et al 2011;Topilina et al 2015a,b;Reitter et al 2016), suggesting that some inteins have evolved to regulate host protein function.…”