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

Abstract

A series of duplication events led to an expansion of clade B Serine Protease Inhibitors (SERPIN), currently displaying a large repertoire of functions in vertebrates. Accordingly, the recent duplicates SERPINB3 and B4 located in human 18q21.3 SERPIN cluster control the activity of different cysteine and serine proteases, respectively. Here, we aim to assess SERPINB3 and B4 coevolution with their target proteases in order to understand the evolutionary forces shaping the accelerated divergence of these duplicates. Phylogenetic analysis of primate sequences placed the duplication event in a Hominoidae ancestor (∼30 Mya) and the emergence of SERPINB3 in Homininae (∼9 Mya). We detected evidence of strong positive selection throughout SERPINB4/B3 primate tree and target proteases, cathepsin L2 (CTSL2) and G (CTSG) and chymase (CMA1). Specifically, in the Homininae clade a perfect match was observed between the adaptive evolution of SERPINB3 and cathepsin S (CTSS) and most of sites under positive selection were located at the inhibitor/protease interface. Altogether our results seem to favour a coevolution hypothesis for SERPINB3, CTSS and CTSL2 and for SERPINB4 and CTSG and CMA1. A scenario of an accelerated evolution driven by host-pathogen interactions is also possible since SERPINB3/B4 are potent inhibitors of exogenous proteases, released by infectious agents. Finally, similar patterns of expression and the sharing of many regulatory motifs suggest neofunctionalization as the best fitted model of the functional divergence of SERPINB3 and B4 duplicates.

SerpinB3 drives cancer stem cell survival in glioblastoma

“…Post-data filtration, our next strongest hit was a cysteine-protease inhibitor, SerpinB3 (also known as squamous cell carcinoma antigen 1 [SCCA1]), which has known roles in tumor progression in cervical, head and neck cancers, and hepatocellular carcinoma (HCC) ( Cannito et al, 2015 ; Pontisso, 2014 ). SerpinB3 has been observed in the cytoplasm and nucleus of cells and is expressed primarily in the esophagus, nasopharynx, and female reproductive organs in normal human physiology ( Gomes et al, 2014 ; Sun et al, 2017 ; Uhlén et al, 2015 ). We validated the binding of SerpinB3 to His-tagged JAM-A ( Figure 1B ).…”

Identification of novel lncRNAs involved in the pathogenesis of childhood acute lymphoblastic leukemia

“…CTSG and CTSS are genes coding for the proteins cathepsin G and cathepsin S, which belong to the cathepsin family (34), and are involved in the immune response. CTSG and CTSS were revealed to be upregulated by lncRNAs NONHSAT134556.2 and NONHSAT027612.2, respectively.…”

SERPINB3 and B4: From biochemistry to biology

“…Two independent studies showed these two genes are frequently co-expressed in same tissues including bladder, uterus, esophagus, lung, prostate, testis, thymus, and trachea, except SERPINB4 was not detectable in bladder and thymus [14, 30]. The clarification of tissue distribution of these two duplicated proteins benefited from the development of specific antibodies, anti-SERPINB3 (clone 8H11) and anti-SERPINB4 (clone 10C12), which was validated using recombinant proteins [30].…”