Abstract
The non-integrin laminin receptor (LAMR1/RPSA) and galectin-3 (Gal-3) are multi-functional host molecules with roles in diverse pathological processes, particularly of infectious or oncogenic origins. Using bimolecular fluorescence complementation and confocal imaging, we demonstrate that the two proteins homo- and heterodimerize, and that each isotype forms a distinct cell surface population. We present evidence that the 37 kDa form of LAMR1 (37LRP) is the precursor of the previously described 67 kDa laminin receptor (67LR), whereas the heterodimer represents an entity that is distinct from this molecule. Site-directed mutagenesis confirmed that the single cysteine (C173) of Gal-3 or lysine (K166) of LAMR1 are critical for heterodimerization. Recombinant Gal-3, expressed in normally Gal-3-deficient N2a cells, dimerized with endogenous LAMR1 and led to a significantly increased number of internalized bacteria (Neisseria meningitidis), confirming the role of Gal-3 in bacterial invasion. Contact-dependent cross-linking determined that, in common with LAMR1, Gal-3 binds the meningococcal secretin PilQ, in addition to the major pilin PilE. This study adds significant new mechanistic insights into the bacterial–host cell interaction by clarifying the nature, role and bacterial ligands of LAMR1 and Gal-3 isotypes during colonization.
Highlights
The non-integrin laminin receptor (LAMR1), commonly referred to as ribosomal protein SA (RPSA), is a highly conserved multi-functional protein that has been localized to the cell surface, the cytosol, the 40S ribosomal subunit and, in histone, chromatin and membrane-associated complexes in the nucleus [1,2,3,4,5,6]
We recently demonstrated that the three major aetiological agents of bacterial meningitis, Neisseria meningitidis, Streptococcus pneumoniae and Haemophilus influenzae, engage LAMR1 on the surface of human cells via specific surface ligands [7]
We showed that monomeric 37LRP, its presumed homodimer 67 kDa laminin receptor (67LR) and the 37LRP/Gal-3 heterodimer coexist as distinct populations on the host cell surface
Summary
The non-integrin laminin receptor (LAMR1), commonly referred to as ribosomal protein SA (RPSA), is a highly conserved multi-functional protein that has been localized to the cell surface, the cytosol, the 40S ribosomal subunit and, in histone, chromatin and membrane-associated complexes in the nucleus [1,2,3,4,5,6]. LAMR1 has been identified as the surface receptor for the Escherichia coli K1 toxin Cfr, a number of viruses, and the cellular prion protein [8,9,10,11,12,13]. LAMR1 has roles in cell viability, adhesion and motility. Elevated LAMR1 expression correlates strongly with increased invasiveness and metastatic potential of cancer cells [2,5,14,15,16]. LAMR1 has important functions in diverse pathological processes, of infectious or oncogenic origins
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