Carbamylated LL-37 as a modulator of the immune response

TY - JOUR

T1 - Carbamylated LL-37 as a modulator of the immune response

AU - Koro, Catalin

AU - Hellvard, Annelie

AU - Delaleu, Nicolas

AU - Binder, Veronika

AU - Scavenius, Carsten

AU - Bergum, Brith

AU - Główczyk, Izabela

AU - Roberts, Helen M

AU - Chapple, Iain Lc

AU - Grant, Melissa M

AU - Rapala-Kozik, Maria

AU - Klaga, Kinga

AU - Enghild, Jan J

AU - Potempa, Jan

AU - Mydel, Piotr

N1 - © The Author(s) 2016.

PY - 2016/4/1

Y1 - 2016/4/1

N2 - Carbamylation of lysine residues and protein N-termini is an ubiquitous, non-enzymatic post-translational modification. Carbamylation at sites of inflammation is due to cyanate formation during the neutrophil oxidative burst and may target lysine residues within the antimicrobial peptide LL-37. The bactericidal and immunomodulatory properties of LL-37 depend on its secondary structure and cationic nature, which are conferred by arginine and lysine residues. Therefore, carbamylation may affect the biological functions of LL-37. The present study examined the kinetics and pattern of LL-37 carbamylation to investigate how this modification affects the bactericidal, cytotoxic and immunomodulatory function of the peptide. The results indicated that LL-37 undergoes rapid modification in the presence of physiological concentrations of cyanate, yielding a spectrum of diverse carbamylated peptides. Mass spectrometry analyses revealed that the N-terminal amino group of Leu-1 was highly reactive and was modified almost instantly by cyanate to generate the predominant form of the modified peptide, named LL-37 C1. This was followed by the sequential carbamylation of Lys-8, Lys-12, and Lys-15 to yield LL-37 C8, and Lys-15 to yield LL-37 C12,15. Carbamylation had profound and diverse effects on the structure and biological properties of LL-37. In some cases, anti-inflammatory LL-37 was rapidly converted to pro-inflammatory LL-37.

AB - Carbamylation of lysine residues and protein N-termini is an ubiquitous, non-enzymatic post-translational modification. Carbamylation at sites of inflammation is due to cyanate formation during the neutrophil oxidative burst and may target lysine residues within the antimicrobial peptide LL-37. The bactericidal and immunomodulatory properties of LL-37 depend on its secondary structure and cationic nature, which are conferred by arginine and lysine residues. Therefore, carbamylation may affect the biological functions of LL-37. The present study examined the kinetics and pattern of LL-37 carbamylation to investigate how this modification affects the bactericidal, cytotoxic and immunomodulatory function of the peptide. The results indicated that LL-37 undergoes rapid modification in the presence of physiological concentrations of cyanate, yielding a spectrum of diverse carbamylated peptides. Mass spectrometry analyses revealed that the N-terminal amino group of Leu-1 was highly reactive and was modified almost instantly by cyanate to generate the predominant form of the modified peptide, named LL-37 C1. This was followed by the sequential carbamylation of Lys-8, Lys-12, and Lys-15 to yield LL-37 C8, and Lys-15 to yield LL-37 C12,15. Carbamylation had profound and diverse effects on the structure and biological properties of LL-37. In some cases, anti-inflammatory LL-37 was rapidly converted to pro-inflammatory LL-37.

KW - Carbamylation

KW - LL-37

KW - immunomodulation

UR - https://www.scopus.com/pages/publications/84979009547

U2 - 10.1177/1753425916631404

DO - 10.1177/1753425916631404

M3 - Journal article

C2 - 26878866

SN - 1753-4259

VL - 22

SP - 218

EP - 229

JO - Innate Immunity

JF - Innate Immunity

IS - 3

ER -