SERPINA2 Is a Novel Gene with a Divergent Function from SERPINA1

Abstract

Serine protease inhibitors (SERPINs) are a superfamily of highly conserved proteins that play a key role in controlling the activity of proteases in diverse biological processes. The SERPIN cluster located at the 14q32.1 region includes the gene coding for SERPINA1, and a highly homologous sequence, SERPINA2, which was originally thought to be a pseudogene. We have previously shown that SERPINA2 is expressed in different tissues, namely leukocytes and testes, suggesting that it is a functional SERPIN. To investigate the function of SERPINA2, we used HeLa cells stably transduced with the different variants of SERPINA2 and SERPINA1 (M1, S and Z) and leukocytes as the in vivo model. We identified SERPINA2 as a 52 kDa intracellular glycoprotein, which is localized at the endoplasmic reticulum (ER), independently of the variant analyzed. SERPINA2 is not significantly regulated by proteasome, proposing that ER localization is not due to misfolding. Specific features of SERPINA2 include the absence of insoluble aggregates and the insignificant response to cell stress, suggesting that it is a non-polymerogenic protein with divergent activity of SERPINA1. Using phylogenetic analysis, we propose an origin of SERPINA2 in the crown of primates, and we unveiled the overall conservation of SERPINA2 and A1. Nonetheless, few SERPINA2 residues seem to have evolved faster, contributing to the emergence of a new advantageous function, possibly as a chymotrypsin-like SERPIN. Herein, we present evidences that SERPINA2 is an active gene, coding for an ER-resident protein, which may act as substrate or adjuvant of ER-chaperones.

RNA-sequencing Identifies Novel Pathways in Sarcoidosis Monocytes

“…Furthermore, we chose the gene encoding cytochrome B-245 β chain that is an integral part of oxidative phosphorylation and its variation has been reported in chronic granulomatous disease 30 . Serpin family member 1 (SERPINA1) encodes peptidase inhibitor clade 1, which is α-antitrypsin precursor 31 . We also chose two genes from ribosomal pathways for validation.…”

Update of the human and mouse SERPINgene superfamily

“…SERPINA2 was initially classified as a pseudogene; however, recent evidence indicates that it produces an active transcript that encodes a protein located in the endoplasmic reticulum [ 18 ]. A study that sequenced SERPINA2 genes across multiple ethnic groups indicated that in addition to active SERPINA2 protein, there is a haplotype characterized by a partial deletion which has patterns suggestive of positive selection for loss-of-function of SERPINA2 protein.…”

Adaptive Evolution and Divergence of SERPINB3: A Young Duplicate in Great Apes

“…SERPINB11 , a highly conserved gene in primates, was lost and resurrected in humans where the accumulation of several mutations contributed to the appearance of a modified non-inhibitory SERPIN, probably linked to an adaptive response against the emergence of infectious diseases in recent human evolution [66] . Also, in SERPINA2 , a 90 MY old duplicate of alpha1-antitrypsin (SERPINA1), several sites seem to be under positive selection in primates, contributing to the emergence of a new advantageous function, possible as a chymotrypsin-like inhibitor [67] . Conversely, a large deletion in SERPINA2 was proposed to be selective advantageous in Africans through a potential role in fertility or in host–pathogen interactions (Seixas, et al 2007).…”