The family of secreted phospholipases A2: from venom to therapeutic enzymes in inflammatory and autoimmune diseases

Il 08/06/2018 ore 14.30 - 15.30

Area della Ricerca Cnr Na1 (sala conferenze), Via P. Castellino, 111 - 80131 Napoli

Dr. Gérard Lambeau from the Institute of molecular and cellular pharmacology, CNRS and Université Côte d'Azur, Valbonne Sophia Antipolis, France, will give a seminar on the role of phospholipases A₂ (sPLA₂s)  in inflammation and associated pathologies. Secreted PLA2s are disulfide-rich low molecular mass (14-19 kDa) enzymes that hydrolyze multiple phospholipids to release free fatty acids and lysophospholipids. sPLA₂s are diverse in nature. They were discovered in snake and insect venoms. Venom sPLA2s exert digestive and toxic functions towards preys but are also endowed with pharmacological and therapeutical properties. More than two decades ago, we started to work on toxic 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 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 act as both enzymes and ligands. We and others cloned several mammalian sPLA₂s, bringing the total number of mammalian sPLA₂s to 12 members. Interestingly, recent evidence indicates that snakes also contain, like humans, a diversity of sPLA₂s in their various tissues, beyond the venom gland.

Since more than a decade, our 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 distributions 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 physiopathological situations, and represent potential drug targets or bioactive drugs. Moreover, PLA2R1 is likely a polymodal receptor with multiple ligands and functions, beyond its interaction with sPLA₂s.

In his talk, he will present some novel biological roles of both venom and mammalian sPLA₂s and of PLA2R1 in host defense, atherosclerosis, sperm fertility, cancer and membranous nephropathy, a rare but severe human auto-immune kidney disease in which PLA2R1 is the major autoantigen. Together, mammalian sPLA₂s and PLA2R1 constitute attractive drug targets and active biomolecules in multiple human diseases. Several phase II and III clinical trials with sPLA2 inhibitors have failed over the years because of the sPLA2 complexity and the use of broadly specific inhibitors inhibiting several sPLA2s at the same time. However, several sPLA2s and PLA2R1 diagnosis tests are now commercially available and can be used in the clinics for cardiovascular diseases and membranous nephropathy.

Organizzato da:
Cnr-Ibp

Referente organizzativo:
Stefania Mariggiò
CNR - Istituto di biochimica delle proteine
Via P. Castellino, 111 - 80131 Napoli
s.mariggio@ibp.cnr.it
081/6132545

Modalità di accesso: ingresso libero