title: A naturally occurring transcript variant of MARCO reveals the SRCR domain is critical for function.
abstract: Macrophage receptor with collagenous structure (MARCO) is a class A scavenger receptor (cA-SR) that recognizes and phagocytoses a wide variety of pathogens. Most cA-SRs that contain a C-terminal scavenger receptor cysteine-rich (SRCR) domain use the proximal collagenous domain to bind ligands. In contrast, the role of the SRCR domain of MARCO in phagocytosis, adhesion and pro-inflammatory signaling is less clear. The discovery of a naturally occurring transcript variant lacking the SRCR domain, MARCOII, provided the opportunity to study the role of the SRCR domain of MARCO. We tested whether the SRCR domain is required for ligand binding, promoting downstream signaling and enhancing cellular adhesion. Unlike cells expressing full-length MARCO, ligand binding was abolished in MARCOII-expressing cells. Furthermore, co-expression of MARCO and MARCOII impaired phagocytic function, indicating that MARCOII acts as a dominant-negative variant. Unlike MARCO, expression of MARCOII did not enhance Toll-like receptor 2 (TLR2)-mediated pro-inflammatory signaling in response to bacterial stimulation. MARCO-expressing cells were more adherent and exhibited a dendritic-like phenotype, whereas MARCOII-expressing cells were less adherent and did not exhibit changes in morphology. These data suggest the SRCR domain of MARCO is the key domain in modulating ligand binding, enhancing downstream pro-inflammatory signaling and MARCO-mediated cellular adhesion.
authors.affiliation: Department of Pathology and Molecular Medicine, McMaster University, Hamilton, Ontario, Canada.
authors.forename: Kyle E
authors.initials: KE
authors.lastname: Novakowski
authors.affiliation: Department of Biochemistry and Biomedical Sciences, McMaster University, Hamilton, Ontario, Canada.
authors.forename: Angela
authors.initials: A
authors.lastname: Huynh
authors.affiliation: Department of Pathology and Molecular Medicine, McMaster University, Hamilton, Ontario, Canada.
authors.forename: SeongJun
authors.initials: S
authors.lastname: Han
authors.affiliation: Department of Pathology and Molecular Medicine, McMaster University, Hamilton, Ontario, Canada.
authors.forename: Michael G
authors.initials: MG
authors.lastname: Dorrington
authors.affiliation: Department of Pathology and Molecular Medicine, McMaster University, Hamilton, Ontario, Canada.
authors.forename: Charles
authors.initials: C
authors.lastname: Yin
authors.affiliation: Department of Pathology and Molecular Medicine, McMaster University, Hamilton, Ontario, Canada.
authors.forename: Zhongyuan
authors.initials: Z
authors.lastname: Tu
authors.affiliation: Department of Microbiology, University of Manitoba, Winnipeg, Manitoba, Canada.
authors.forename: Peter
authors.initials: P
authors.lastname: Pelka
authors.affiliation: Department of Pathology and Molecular Medicine, McMaster University, Hamilton, Ontario, Canada.
authors.forename: Peter
authors.initials: P
authors.lastname: Whyte
authors.affiliation: Department of Biochemistry and Biomedical Sciences, McMaster University, Hamilton, Ontario, Canada.
authors.forename: Alba
authors.initials: A
authors.lastname: Guarné
authors.affiliation: Department of Pathology, College of Veterinary Medicine, University of Georgia, Athens, GA, USA.
authors.forename: Kaori
authors.initials: K
authors.lastname: Sakamoto
authors.affiliation: Department of Pathology and Molecular Medicine, McMaster University, Hamilton, Ontario, Canada.
authors.forename: Dawn M E
authors.initials: DM
authors.lastname: Bowdish
mesh_terms: D017398:Alternative Splicing / Q000235:genetics*; D000595:Amino Acid Sequence; D000818:Animals; D002448:Cell Adhesion; D048430:Cell Shape; D003001:Cloning, Molecular; D004705:Endocytosis; D057809:HEK293 Cells; D006801:Humans; D008024:Ligands; D018950:Lipopolysaccharide Receptors / Q000378:metabolism; D008810:Mice, Inbred C57BL; D016328:NF-kappa B / Q000378:metabolism; D000072417:Protein Domains; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D011971:Receptors, Immunologic / Q000737:chemistry* / Q000235:genetics* / Q000378:metabolism; D013296:Streptococcus pneumoniae / Q000502:physiology; D013329:Structure-Activity Relationship; D051195:Toll-Like Receptor 2 / Q000378:metabolism
chemical_list: D008024:Ligands; D018950:Lipopolysaccharide Receptors; C490460:MARCO protein, human; D016328:NF-kappa B; D012333:RNA, Messenger; D011971:Receptors, Immunologic; D051195:Toll-Like Receptor 2