title: A Lys49 phospholipase A2, isolated from Bothrops asper snake venom, induces lipid droplet formation in macrophages which depends on distinct signaling pathways and the C-terminal region.
abstract: MT-II, a Lys49PLA2 homologue devoid of catalytic activity from B. asper venom, stimulates inflammatory events in macrophages. We investigated the ability of MT-II to induce formation of lipid droplets (LDs), key elements of inflammatory responses, in isolated macrophages and participation of protein kinases and intracellular PLA2s in this effect. Influence of MT-II on PLIN2 recruitment and expression was assessed, and the effects of some synthetic peptides on LD formation were further evaluated. At noncytotoxic concentrations, MT-II directly activated macrophages to form LDs. This effect was reproduced by a synthetic peptide corresponding to the C-terminal sequence 115-129 of MT-II, evidencing the critical role of C-terminus for MT-II-induced effect. Moreover, MT-II induced expression and recruitment of PLIN2. Pharmacological interventions with specific inhibitors showed that PKC, PI3K, ERK1/2, and iPLA2, but not P38(MAPK) or cPLA2, signaling pathways are involved in LD formation induced by MT-II. This sPLA2 homologue also induced synthesis of PGE2 that colocalized to LDs. In conclusion, MT-II is able to induce formation of LDs committed to PGE2 formation in a process dependent on C-terminal loop engagement and regulated by distinct protein kinases and iPLA2. LDs may constitute an important inflammatory mechanism triggered by MT-II in macrophages.
authors.affiliation: Laboratory of Pharmacology, Butantan Institute, Avenida Vital Brazil, 05503-900 São Paulo, SP, Brazil.
authors.forename: Karina Cristina
authors.initials: KC
authors.lastname: Giannotti
authors.forename: Elbio
authors.initials: E
authors.lastname: Leiguez
authors.forename: Vanessa
authors.initials: V
authors.lastname: Moreira
authors.forename: Neide Galvão
authors.initials: NG
authors.lastname: Nascimento
authors.forename: Bruno
authors.initials: B
authors.lastname: Lomonte
authors.forename: José Maria
authors.initials: JM
authors.lastname: Gutiérrez
authors.forename: Robson
authors.initials: R
authors.lastname: Lopes de Melo
authors.forename: Catarina
authors.initials: C
authors.lastname: Teixeira
mesh_terms: D000818:Animals; D017837:Bothrops; D002384:Catalysis; D002470:Cell Survival; D008055:Lipids / Q000737:chemistry*; D008239:Lysine / Q000737:chemistry; D008264:Macrophages / Q000166:cytology / Q000378:metabolism*; D008297:Male; D051379:Mice; D010455:Peptides / Q000737:chemistry; D054467:Phospholipases A2 / Q000737:chemistry*; D011494:Protein Kinases / Q000378:metabolism; D017434:Protein Structure, Tertiary; D015398:Signal Transduction; D012910:Snake Venoms / Q000201:enzymology*
chemical_list: D008055:Lipids; D010455:Peptides; D012910:Snake Venoms; D011494:Protein Kinases; D054467:Phospholipases A2; D008239:Lysine