A Novel Protein Isoform of the Multicopy Human NAIP Gene Derives from Intragenic Alu SINE Promoters

Abstract

The human neuronal apoptosis inhibitory protein (NAIP) gene is no longer principally considered a member of the Inhibitor of Apoptosis Protein (IAP) family, as its domain structure and functions in innate immunity also warrant inclusion in the Nod-Like Receptor (NLR) superfamily. NAIP is located in a region of copy number variation, with one full length and four partly deleted copies in the reference human genome. We demonstrate that several of the NAIP paralogues are expressed, and that novel transcripts arise from both internal and upstream transcription start sites. Remarkably, two internal start sites initiate within Alu short interspersed element (SINE) retrotransposons, and a third novel transcription start site exists within the final intron of the GUSBP1 gene, upstream of only two NAIP copies. One Alu functions alone as a promoter in transient assays, while the other likely combines with upstream L1 sequences to form a composite promoter. The novel transcripts encode shortened open reading frames and we show that corresponding proteins are translated in a number of cell lines and primary tissues, in some cases above the level of full length NAIP. Interestingly, some NAIP isoforms lack their caspase-sequestering motifs, suggesting that they have novel functions. Moreover, given that human and mouse NAIP have previously been shown to employ endogenous retroviral long terminal repeats as promoters, exaptation of Alu repeats as additional promoters provides a fascinating illustration of regulatory innovations adopted by a single gene.

Structural variants caused by Alu insertions are associated with risks for many human diseases

“…Although this model has not been proven for polymorphic Alu elements, it is supported for evolutionarily older elements that are fixed in the genome, including Alu elements that act as tissue-specific enhancers (e.g., refs. 71,72). Fixed Alu can also provide alternatively used exons (e.g., refs.…”

Extensive relationship between antisense transcription and alternative splicing in the human genome

“…In general, however, antisense transcription was positively associated with longer genes, at both known and novel SAS loci. This association is not surprising, since longer genomic regions are more likely, simply by chance, to accrue functional promoter sequences, for instance, from transposable element (TE) insertions that can drive both coding and noncoding RNA transcription in the antisense orientation (Faulkner et al 2009;Romanish et al 2009). We speculate that antisense transcription arising by chance can be consequently selected for as a means of increasing the variety of isoforms expressed from novel SAS genes.…”

Epithelial NAIPs protect against colonic tumorigenesis

“…Humans also have several NAIP genes, only one of which is full length (Schmutz et al, 2004;Romanish et al, 2009). NAIPs are intracellular, cytosolic proteins with a tripartite structure; three N-terminal baculovirus inhibitor of apoptosis (IAP) protein repeat (BIR) domains, a central NACHT domain and C-terminal leucine rich-repeat (LRR) domains.…”