DNA-mediated proteolysis by neutrophil elastase enhances binding activities of the HMGB1 protein

Abstract

Neutrophil extracellular traps (NETs) are produced through ejection of genomic DNA by neutrophils into extracellular space and serve as a weapon to fight against pathogens. Neutrophil elastase, a serine protease loaded on NETs, attacks and kills pathogens, while extracellular high-mobility-group-box-1 (HMGB1) protein serves as a danger signal to other cells. How the action of these factors is coordinated as part of the innate immune response is not fully understood. In this article, using biochemical and biophysical approaches, we demonstrate that DNA mediates specific proteolysis of HMGB1 by neutrophil elastase and that the proteolytic processing remarkably enhances binding activities of extracellular HMGB1. Through the DNA-mediated proteolysis of HMGB1 by neutrophil elastase, the negatively charged segment containing D/E repeats is removed from HMGB1. This proteolytic removal of the C-terminal tail causes a substantial increase in binding activities of HMGB1 because the D/E repeats are crucial for dynamic autoinhibition via electrostatic interactions. Our data on the oxidized HMGB1 (i.e., ‘disulfide HMGB1’) protein show that the truncation substantially increases HMGB1’s affinities for the toll-like receptor TLR4•MD-2 complex, DNA G-quadruplex, and the Holliday junction DNA structure. The DNA-mediated proteolysis of HMGB1 by neutrophil elastase in NETs may promote the function of extracellular HMGB1 as a damage-associated molecular pattern that triggers the innate immune response of nearby cells. Neutrophil extracellular traps (NETs) are produced through ejection of genomic DNA by neutrophils into extracellular space and serve as a weapon to fight against pathogens. Neutrophil elastase, a serine protease loaded on NETs, attacks and kills pathogens, while extracellular high-mobility-group-box-1 (HMGB1) protein serves as a danger signal to other cells. How the action of these factors is coordinated as part of the innate immune response is not fully understood. In this article, using biochemical and biophysical approaches, we demonstrate that DNA mediates specific proteolysis of HMGB1 by neutrophil elastase and that the proteolytic processing remarkably enhances binding activities of extracellular HMGB1. Through the DNA-mediated proteolysis of HMGB1 by neutrophil elastase, the negatively charged segment containing D/E repeats is removed from HMGB1. This proteolytic removal of the C-terminal tail causes a substantial increase in binding activities of HMGB1 because the D/E repeats are crucial for dynamic autoinhibition via electrostatic interactions. Our data on the oxidized HMGB1 (i.e., ‘disulfide HMGB1’) protein show that the truncation substantially increases HMGB1’s affinities for the toll-like receptor TLR4•MD-2 complex, DNA G-quadruplex, and the Holliday junction DNA structure. The DNA-mediated proteolysis of HMGB1 by neutrophil elastase in NETs may promote the function of extracellular HMGB1 as a damage-associated molecular pattern that triggers the innate immune response of nearby cells. In mammalian tissues, DNA in the extracellular space may represent a danger associated with infection or tissue damage (1Pisetsky D.S. The origin and properties of extracellular DNA: from PAMP to DAMP.Clin. Immunol. 2012; 144: 32-40Crossref PubMed Scopus (139) Google Scholar, 2Shi C. Yang L. Braun A. Anders H.J. Extracellular DNA-A danger signal triggering immunothrombosis.Front. Immunol. 2020; 11: 568513Crossref PubMed Scopus (21) Google Scholar). 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DNA fragments and some DNA-binding proteins released to extracellular space serve as damage-associated molecular patterns (DAMPs) that activate some cell surface receptors and initiate innate immune response of nearby cells (8Gong T. Liu L. Jiang W. Zhou R. DAMP-sensing receptors in sterile inflammation and inflammatory diseases.Nat. Rev. Immunol. 2020; 20: 95-112Crossref PubMed Scopus (505) Google Scholar, 9Kaczmarek A. Vandenabeele P. Krysko D.V. Necroptosis: the release of damage-associated molecular patterns and its physiological relevance.Immunity. 2013; 38: 209-223Abstract Full Text Full Text PDF PubMed Scopus (862) Google Scholar). The high-mobility-group-box-1 (HMGB1) protein is one of the most potent DAMPs in mammals and plays several important roles in innate immunity involving extracellular DNA. Although HMGB1 typically serves as a chromatin-associated protein that bends DNA (10Malarkey C.S. Churchill M.E.A. The high mobility group box: the ultimate utility player of a cell.Trends Biochem. Sci. 2012; 37: 553-562Abstract Full Text Full Text PDF PubMed Scopus (125) Google Scholar, 11Thomas J.O. Stott K. H1 and HMGB1: modulators of chromatin structure.Biochem. Soc. Trans. 2012; 40: 341-346Crossref PubMed Scopus (82) Google Scholar), HMGB1 is released to extracellular space not only passively from dying cells but also actively from platelets and some healthy cells (e.g., macrophages, astrocytes, and dendritic cells) (12Chen R. Kang R. Tang D. The mechanism of HMGB1 secretion and release.Exp. Mol. Med. 2022; 54: 91-102Crossref PubMed Scopus (35) Google Scholar, 13Raucci A. Palumbo R. Bianchi M.E. HMGB1: a signal of necrosis.Autoimmunity. 2007; 40: 285-289Crossref PubMed Scopus (155) Google Scholar). Extracellular HMGB1 can destabilize scaffold DNA matrix of bacterial biofilm (14Devaraj A. Novotny L.A. Robledo-Avila F.H. Buzzo J.R. Mashburn-Warren L. Jurcisek J.A. et al.The extracellular innate-immune effector HMGB1 limits pathogenic bacterial biofilm proliferation.J. Clin. Invest. 2021; 131e140527Crossref PubMed Scopus (5) Google Scholar). Extracellular HMGB1 is also involved in endocytosis of extracellular DNA into cells (15de Mingo Pulido Á. Hänggi K. Celias D.P. Gardner A. Li J. Batista-Bittencourt B. et al.The inhibitory receptor TIM-3 limits activation of the cGAS-STING pathway in intra-tumoral dendritic cells by suppressing extracellular DNA uptake.Immunity. 2021; 54: 1154-1167.e7Abstract Full Text Full Text PDF PubMed Scopus (40) Google Scholar, 16Lu J. Yue Y. Xiong S. Extracellular HMGB1 augments macrophage inflammation by facilitating the endosomal accumulation of ALD-DNA via TLR2/4-mediated endocytosis.Biochim. Biophys. Acta Mol. Basis Dis. 2021; 1867: 166184Crossref PubMed Scopus (9) Google Scholar). Interactions between extracellular HMGB1 and immune receptor TIM-3 the DNA (15de Mingo Pulido Á. Hänggi K. Celias D.P. 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In this article, we demonstrate that DNA enhances and in the proteolytic of HMGB1 by neutrophil HMGB1 is a protein and a between and in extracellular space D. P. Y. J. properties of the of the HMGB1 PubMed Scopus (35) Google Scholar, J. A. J. S. structural in the of HMGB1 and its for the binding to Biophys. 2013; PubMed Scopus Google Scholar, L. D. K. P. K. et of group (HMGB1) in extracellular by in protein 2013; Full Text Full Text PDF PubMed Scopus Google Scholar). The oxidized HMGB1 protein (i.e., often to as ‘disulfide HMGB1’) in biochemical and biophysical because this of HMGB1 is to the extracellular function the HMGB1 show that the DNA-mediated proteolysis of HMGB1 at the between the and the C-terminal D/E this proteolysis causes a increase in the binding affinities of HMGB1 for G-quadruplex Holliday junction and TLR4•MD-2 the DNA-mediated proteolysis of HMGB1 by neutrophil elastase in NETs may important in on is we that DNA the proteolysis of HMGB1 by neutrophil this HMGB1 proteins by neutrophil elastase in the and of DNA. the for the at some In the of DNA the proteolysis of HMGB1 by neutrophil elastase from the as as in in the of DNA to the in the of DNA and and in the data show that DNA enhances the and in the proteolytic of HMGB1 by neutrophil Through we the of the DNA-mediated the of DNA we the DNA for the of the Through of we the of the proteolysis the as D. and of at the for the proteolysis of HMGB1 at in the and of the DNA the HMGB1 of the we the and the the of these for the in the and of DNA. The to a that the of D. and of at the Scholar). in the of HMGB1 proteolysis by neutrophil elastase is increased by as as in the of and for the proteolysis of HMGB1 by neutrophil elastase in the and of at The at a of DNA with a of at The at a of DNA with a of in a The data of and into DNA the HMGB1 by neutrophil The of DNA a in the by a of This that DNA increases the of between neutrophil elastase and through a DNA can also release the involving the C-terminal tail HMGB1 X. B. Y. et autoinhibition of the HMGB1 protein via electrostatic of Mol. 2021; PubMed Scopus Google Scholar). to the data for of by neutrophil elastase in the neutrophil elastase from PubMed Scopus Google Scholar, C. action of neutrophil and elastase on of on 2003; Full Text Full Text PDF PubMed Scopus Google Scholar), are the for the in the of DNA is for the by neutrophil data the that the in is important for the DNA-mediated proteolysis by neutrophil we that the also in the of DNA. The structures of neutrophil elastase show that the of this serine protease is from the charged surface in the is that neutrophil elastase the charged surface to with DNA. The DNA binding the and the a HMGB1 the D/E repeats but the a proteolysis by neutrophil elastase in the that the charged surface of the neutrophil elastase may also to electrostatic to a in the and of HMGB1 by neutrophil on of neutrophil elastase that this serine protease only S. of neutrophil elastase, and with but and Immunol. PubMed Scopus Google Scholar, P. H. et of for neutrophil elastase through Natl. Acad. Sci. U. S. A. PubMed Scopus Google Scholar). This to the on HMGB1 from its to the of HMGB1 with neutrophil elastase in the and of DNA. of neutrophil HMGB1 in the of DNA high of and C-terminal and and a to C-terminal also in the with the and in the the of these through of HMGB1 and of and by data that the of the DNA-mediated proteolysis of HMGB1 by neutrophil elastase is also the for for the HMGB1 proteolysis in the of DNA. The data show the and to the DNA-mediated the for and the of In in the in the of the of the for the in the of DNA. that the proteolysis of HMGB1 by neutrophil elastase in the of DNA is not only but also is the of the DNA-mediated proteolysis of HMGB1 by neutrophil elastase, we a protein and its molecular properties to of the HMGB1 Through we the to the proteolytic truncation the DNA-binding affinities of HMGB1 for a DNA G-quadruplex J. 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Invest. 2021; 131e140527Crossref PubMed Scopus (5) Google and HMGB1 is to with these atypical DNA structures (14Devaraj A. Novotny L.A. Robledo-Avila F.H. Buzzo J.R. Mashburn-Warren L. Jurcisek J.A. et al.The extracellular innate-immune effector HMGB1 limits pathogenic bacterial biofilm proliferation.J. Clin. Invest. 2021; 131e140527Crossref PubMed Scopus (5) Google Scholar, J. A. et to the a player in 54: PubMed Google Scholar, J. L. D. S. P. et into G-quadruplex DNA by HMGB1 2019; PubMed Scopus Google Scholar, J.O. binding of the of to junction DNA is by the Mol. PubMed Scopus Google Scholar, M.E. of DNA by protein PubMed Scopus Google Scholar, H. S. 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PubMed Scopus Google Scholar). the to the removal of the C-terminal tail HMGB1’s with TLR4•MD-2 complex, we the for the HMGB1 protein and the The data are in to the HMGB1 the a increase in response at in the The from the data for the HMGB1 protein and for the of for TLR4•MD-2 that of the HMGB1 protein by a of as by the and the the of is by the Our data show that the DNA-mediated proteolysis of HMGB1 by neutrophil elastase enhances the binding of HMGB1 for the TLR4•MD-2 The via the truncation of HMGB1 by neutrophil elastase can in of autoinhibition of HMGB1. The C-terminal of HMGB1 are negatively charged D/E repeats of or between the negatively charged D/E repeats and the charged (e.g., and autoinhibition that DNA-binding X. B. Y. et autoinhibition of the HMGB1 protein via electrostatic of Mol. 2021; PubMed Scopus Google Scholar). D/E repeats are in proteins J. Y. charged are and important Mol. 2022; PubMed Scopus Google and autoinhibition via with charged X. B. 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J. of at 2020; PubMed Scopus Google Scholar), the negatively charged DNA and the negatively charged C-terminal tail can for the charged DNA-binding (i.e., and The proteolytic removal of the D/E repeats the autoinhibition and promote the binding activities of HMGB1. HMGB1 also the we on and proteins of HMGB1. to HMGB1 only for the that the in the not the other of the protein in the of the for the and proteins at and for the and proteins as the of the in the or the proteins that the negatively charged D/E repeats with the charged in the protein of HMGB1 at physiological The between the C-terminal tail and the DNA-binding also the for neutrophil HMGB1 to the C-terminal tail is from the DNA-binding This may the and the proteolytic processing of HMGB1 by neutrophil Our that DNA mediates the proteolytic processing of HMGB1 by neutrophil elastase and the and this proteolytic processing enhances binding affinities of HMGB1 for its extracellular The from the proteolytic removal of the segment containing the D/E repeats that dynamic The binding as as the removal of the may a in innate immune response involving HMGB1. roles of the DNA-mediated proteolytic processing of HMGB1 by neutrophil elastase in The segment removed from HMGB1 by neutrophil elastase contains not only the D/E repeats but also the signal and a part of the binding for the receptor for is that the HMGB1 truncation the with as as into The of HMGB1’s binding affinities for may increase the of HMGB1 as a that other cells. that HMGB1 is involved in DNA by some cells (15de Mingo Pulido Á. Hänggi K. Celias D.P. Gardner A. Li J. Batista-Bittencourt B. et al.The inhibitory receptor TIM-3 limits activation of the cGAS-STING pathway in intra-tumoral dendritic cells by suppressing extracellular DNA uptake.Immunity. 2021; 54: 1154-1167.e7Abstract Full Text Full Text PDF PubMed Scopus (40) Google Scholar, 16Lu J. Yue Y. Xiong S. Extracellular HMGB1 augments macrophage inflammation by facilitating the endosomal accumulation of ALD-DNA via TLR2/4-mediated endocytosis.Biochim. Biophys. Acta Mol. Basis Dis. 2021; 1867: 166184Crossref PubMed Scopus (9) Google Scholar, S. H. H. H. et innate immune through between the receptor TIM-3 and the Immunol. 2012; PubMed Scopus Google Scholar), that the increase in DNA-binding of HMGB1 endocytosis of extracellular DNA. This may of DNA (e.g., scaffold DNA in bacterial by DNA involved in innate of by the DNA of DNA HMGB1 via its to DNA L. B. D. C. D. et and DNA by PubMed Scopus (225) Google Scholar). that the removal of the C-terminal tail from HMGB1 causes DNA J. A. binding to protein DNA by the PubMed Scopus (40) Google Scholar). the DNA-mediated proteolysis of HMGB1 by neutrophil elastase also promote The in that HMGB1 and neutrophil elastase may This is important because neutrophil elastase and HMGB1 as for inflammatory U. W. Extracellular HMGB1: a in inflammation Med. 2020; PubMed Scopus Google Scholar, B. F. Neutrophil elastase, and as in Rev. PubMed Scopus Google Scholar, U. HMGB1 is a for sterile inflammation and Rev. Immunol. PubMed Scopus Google Scholar). of HMGB1 through the proteolytic processing by neutrophil elastase causes inflammatory of neutrophil elastase may a to HMGB1’s In of inflammatory of HMGB1 also because extracellular HMGB1 neutrophils and causes to NETs involving neutrophil elastase S. H. R. P. et in is by HMGB1 through release of traps and PubMed Scopus Google Scholar, Jiang S. Yang H. et neutrophil extracellular through with toll-like receptor J. Mol. 2013; PubMed Scopus (205) Google Scholar). into the of DNA-mediated proteolysis of HMGB1 by neutrophil elastase to the inflammatory and from neutrophil elastase from TLR4•MD-2 from DNA from DNA of G-quadruplex DNA with a of to in et J. A. et to the a player in 54: PubMed Google Scholar), from DNA The of the DNA with a from DNA and using The Holliday junction DNA of by et junction from Scopus Google and The to the of the DNA using of of the the Holliday junction DNA by The DNA from and to DNA fragments with of HMGB1 in using a the of The protein from using and as X. B. Y. et autoinhibition of the HMGB1 protein via electrostatic of Mol. 2021; PubMed Scopus Google Scholar). the or proteins in containing and as the and The the HMGB1 and using a by a at or The in and using and as for the X. B. Y. et autoinhibition of the HMGB1 protein via electrostatic of Mol. 2021; PubMed Scopus Google Scholar). of neutrophil elastase in a of with The into and at The for the proteolysis of HMGB1 by neutrophil elastase in the and of the DNA or DNA at a in a of and The of neutrophil elastase with a to and with protein into and with to of 2012; PubMed Scopus Google for The in from the of the of the HMGB1 The as the D. and of at the as is the (i.e., the of The and through the to the data with the the proteolysis for and the of HMGB1 by neutrophil elastase in the or of the DNA the The by and at for the with a of and and by to the of using a and a by a with the to using of the protein to as R. C. to 2022; PubMed Scopus Google Scholar). data and using using a of to the of affinities of HMGB1 and its for DNA or Holliday junction using with using of and of at The binding for in a of and The of The binding for Holliday junction in a of and The of junction The from the data using as L. D. J. of by in DNA J. Full Text Full Text PDF PubMed Scopus Google Scholar). The of The with a from a the data for the and truncation HMGB1 for the binding of HMGB1 to TLR4•MD-2 using a in the as by et Bianchi M.E. Y. the mechanism of the by surface Med. PubMed Scopus Google Scholar). of TLR4•MD-2 in a of at and in at of TLR4•MD-2 in The a using for to the The cell and the cell with a on and The of TLR4•MD-2 at a of and the response The for the between HMGB1 and TLR4•MD-2 in a of and The protein and for the HMGB1 protein and and for the The protein at a of at The for the to and the for the for The the and the with a binding using the HMGB1 the The with a from a the data for the and truncation HMGB1 The with as L. D. K. P. K. et of group (HMGB1) in extracellular by in protein 2013; Full Text Full Text PDF PubMed Scopus Google Scholar). The between the C-terminal D/E repeats and through of between the HMGB1 and The for the oxidized proteins using and J. and Scholar). The using a at the of The data with F. S. J. A. a processing on PubMed Scopus Google and the with the W. for PubMed Scopus Google Scholar). The data for the and HMGB1 proteins to and of with protein or in a containing to and of and a in with a of in the of The to for the on high of as a function of and PubMed Scopus Google Scholar). and K. R. K. by of and indicates to structures of in Natl. Acad. Sci. U. S. A. PubMed Scopus Google at to the signal from as the a and represent and from the of the and proteins at of to the data using as X. B. Y. et autoinhibition of the HMGB1 protein via electrostatic of Mol. 2021; PubMed Scopus Google Scholar). data are the or the This contains The that of with the of this and for and for on and for of the at of of the with J. X. A. and J. X. K. and A. B. X. A. and J. X. K. A. and J. This by J. from the of and J. from the The at of is in part by from of The is the of the and not represent the of the of

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