Abstract
In vertebrates, PIAS genes encode versatile cellular regulators, with functions extremely complex and redundant. Here we try to understand their functions from an evolutionary perspective. we evaluate the sequences, expression and molecular functions of amphioxus PIAS genes and compare them with their vertebrate counterparts. Phylogenetic analysis suggests a single PIAS gene in ancestral chordates, which has been duplicated into four families (PIAS1-4) in vertebrates by 2R-WGD but remained single in a basal chordate (amphioxus). Amphioxus PIAS encodes two variants with and without a Serine/Threonine-rich tail, which are retained in human PIAS1-3 but lost in PIAS4. We show that amphioxus PIAS binds C-terminus of NF-κB Rel and blocks the DNA binding activity. In humans, such function is retained in PIAS1, altered in PIAS4, and lost in PIAS2-3. Instead, PIAS3 has evolved new ability to inhibit Rel by binding RHD and promoting SUMOylation. We show that amphioxus PIAS also inhibits NF-κB by binding with upstream signalling adaptor TICAM-like and MyD88. Finally, we verify that human PIAS1, 3 and 4, but not 2, were capable of these newly-discovered functions. Our study offers insight into the sub- and neo-functionalization of PIAS genes and suggests a conserved ancient role for chordate PIAS in NF-κB signalling.
Highlights
Protein inhibitors of activated STATs (PIAS) are versatile cellular regulators[1,2,3]
Our study on amphioxus PIAS reveals some new functions of PIAS genes and offers insight into the functional consequences regarding the evolution of vertebrate PIAS genes
We examined the draft genomes and transcriptomes of three amphioxus species (Branchiostoma japonicum, B. belcheri and B. floridae) and confirmed that there is only one single PIAS gene orthologue
Summary
Protein inhibitors of activated STATs (PIAS) are versatile cellular regulators[1,2,3]. There are four PIAS gene families in vertebrates, including PIAS1, PIAS2 (PIASx), PIAS3 and PIAS4 (PIASy)[4,5,6,7,8] These families have been proposed to regulate the function of over 60 proteins[1], and these regulations are conducted through various molecular mechanisms[9]. PIAS proteins are notorious for functional redundancy Both PIAS1 and PIAS4 inhibit STAT1 and PLAG15,12,13; both PIAS1 and PIAS2 regulate SMAD4, p53, p73, JUN, MDM2, AR and C/EBPε1; and PIAS2, PIAS3 and PIAS4 suppress C/EBPδ14. The study of vertebrate PIAS genes has been hindered by functional complexity and redundancy. Our study on amphioxus PIAS reveals some new functions of PIAS genes and offers insight into the functional consequences regarding the evolution of vertebrate PIAS genes
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