Concluding Remarks and Future Perspectives

Since the first report of the multifunctional nature of the surface-exported S. pyogenes GAPDH/SDH, there has been an explosion of interest in understanding the novel role of GAPDH and other anchorless surface proteins that are associated with virulence in many bacteria, especially pathogens. Together, the contributions of these reports have established that GAPDH plays a critical role in the regulation of virulence. Several attributes of SDH have demonstrated that the surface export of SDH helps GAS adhere to, invade, hide within, and kill the host cell. Surprisingly, SDH also regulates the expression of GAS virulence factors. This “double-edged” sword effect indicates that SDH is a virulence- factor-regulating virulence factor.

It is at the same time intriguing that SDH/GAPDH is endowed with numerous functions and perplexing that the surface export mechanism of SDH/ GAPDH has remained unidentified. One explanation could be that GAPDH is a quintessential protein. The multifunctional nature of GAPDH has allowed many primordial organisms to evolve successfully by performing a variety of new functions until a dedicated protein/enzyme evolves to perform a specific function. Because many cellular functions are environmentally regulated, SDH/ GAPDH may be playing a “proxy role” to maintain uninterrupted cellular function and promote bacterial survival and successful proliferation. In the future, we may identify more functions that are performed by SDH/GAPDH, including its role in epigenetics. For some bacteria, including S. pyogenes, GAPDH appears to be a protective antigen. However, the association of this protein with autoimmune diseases may raise questions. Despite these caveats, SDH/GAPDH remains an amazing candidate molecule for prokaryotic and eukaryotic fundamental, applied, and translational research.