SERPINA2 is a novel gene with a divergent function from SERPINA1

PLoS One. 2013 Jun 24;8(6):e66889. doi: 10.1371/journal.pone.0066889. Print 2013.

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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Endoplasmic Reticulum / drug effects
  • Endoplasmic Reticulum / metabolism
  • Gene Expression Profiling
  • Genetic Variation* / drug effects
  • HeLa Cells
  • Heat-Shock Response / drug effects
  • Humans
  • Likelihood Functions
  • Models, Molecular
  • Molecular Chaperones / metabolism
  • Phylogeny
  • Polymerization / drug effects
  • Proteasome Inhibitors / pharmacology
  • Protein Binding / drug effects
  • Protein Folding / drug effects
  • Protein Transport / drug effects
  • Proteolysis / drug effects
  • Recombinant Proteins / metabolism
  • Subcellular Fractions / drug effects
  • Subcellular Fractions / metabolism
  • alpha 1-Antitrypsin / genetics*
  • alpha 1-Antitrypsin / metabolism

Substances

  • Molecular Chaperones
  • Proteasome Inhibitors
  • Recombinant Proteins
  • SERPINA1 protein, human
  • SERPINA2 protein, human
  • alpha 1-Antitrypsin

Grant support

This work was supported by the Portuguese Foundation for Science and Technology (FCT), project grant to SS – PTDC/SAU-GMG/64043/2006. PIM (SFRH/BD/68940/2010), ZF (SFRH/BD/45907/2008), JF (SFRH/BD/43763/2008), PC (SFRH/BPD/26553/2006), and JSC (SFRH/BPD/48765/2008) are supported by FCT fellowships and funded by POPH-QREN – Promotion of scientific employment, supported by the European Social Fund and national funds of the Ministry of Education and Science. SS and RMH are supported by the programme “Ciência 2007”, financed by the POPH-QREN – Promotion of scientific employment, co-financed by the European Social Fund and national funds of the Ministry of Education and Science. Institute of Molecular Pathology and Immunology of the University of Porto is an Associate Laboratory of the Portuguese Ministry of Education and Science and is partially supported by FCT. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.