Secreted phospholipases A2 (sPLA2s) are disulfide-rich low molecular mass (14-19 kDa) enzymes that hydrolyze phospholipids to release free fatty acids and lysophospholipids. sPLA2s are diverse in nature. They were initially discovered in snake and insect venoms. Venom sPLA2s exert digestive and toxic functions towards preys but are also endowed with pharmacological and potential therapeutical properties. More than two decades ago, we started to work on venom sPLA2s and discovered specific sPLA2 receptors (M and N) including the so-called M-type receptor or PLA2R1, a 180 kDa C-type lectin membrane receptor.

Because of the large structural and functional diversity of venom sPLA2s, we hypothesized that a similar diversity of sPLA2s might exist in mammals. These mammalian sPLA2s would exert their functions as enzymes but also endogenous ligands of the above receptors identified with venom sPLA2s, bringing the concept that sPLA2s may function as both enzymes and ligands. We and others have cloned several mammalian sPLA2s, bringing their total number to 12 isoforms. Interestingly, recent evidence indicates that snakes also contain, like humans, a diversity of sPLA2s in their various tissues, beyond those identified in the venom gland.

Since about two decades, the main challenge is to identify the biological roles of the different sPLA2s and their receptors in physiological and pathophysiological conditions. Like venom sPLA2s, mammalian sPLA2s are not functional isoforms. They are diverse in structure, tissue distribution and enzymatic properties, suggesting distinct functions. Several of them also bind to specific proteins including PLA2R1, which may serve to inhibit or promote sPLA2 action. It is now clear that individual sPLA2s are involved in diverse physiological settings through enzymatically-dependent and -independent mechanisms, act redundantly or non-redundantly in pathophysiological conditions, and represent potential drug targets or bioactive drugs. Moreover, PLA2R1 is likely a polymodal receptor with multiple ligands and functions, beyond interaction with sPLA2s.

In this talk, I will present some biological roles of both venom and mammalian sPLA2s and of PLA2R1 in host defense, atherosclerosis, sperm fertility, and membranous nephropathy, a rare but severe human autoimmune kidney disease in which PLA2R1 was identified as the major autoantigen. Together, mammalian sPLA2s and PLA2R1 constitute attractive drug targets and active biomolecules in multiple human diseases.

*This seminar is also part of the wider University of Bristol Festival of International Research and Partnerships, 19 April-19 May 2021*