Uncovering the evolutionary tail of GZMM: An NSP4 related protease

Serine proteases are the most predominant class performing a number of activities in organisms. Undergoing several mutations in their sequence over a span of a billion years yet S1 chymotrypsin/trypsin family has maintained a common fold. Granule Associated Serine Peptidases of Immune Defense (GASPIDS) belonging to the S1 class, found in the granules of immune cells are explicitly involved in the regulation of immune-related functions possessing a conserved catalytic triad Ser-Asp-His. The neutrophils along with other cells express four serine proteases (ELA2, PR3, CTSG and NSP4) sharing certain common characteristics. Similarly, CTLs and NK cells express a set of proteases, Granzymes. This study infers an evolutionary relationship among GASPIDs. We employed computational strategies and found that a higher degree of similarity existed between NSP4 and GZMM as compared to their members i.e. NSPs and granzymes, respectively. Similarly, GZMM a protease of NK cells and t cells lineage is found in the Met-ase locus consisting of NSPs genes i.e., Ela2, Prtn3 and Ctsg. The evolutionary relationship of Prss57/NSP4 and gzmm/GZMM was reconstructed through empirical phylogenetic analysis which revealed Prss57/NSP4 to be closely related to gzmm/GZMM. Additional co-expression analysis was carried out to determine the regulatory role of Prss57, inducing Gzmm. From this work, we inferred that Prss57/NSP4 is closely related to Gzmm/GZMM.