title: Subtilase cytotoxin cleaves newly synthesized BiP and blocks antibody secretion in B lymphocytes.
abstract: Shiga-toxigenic Escherichia coli (STEC) use subtilase cytotoxin (SubAB) to interfere with adaptive immunity. Its inhibition of immunoglobulin secretion is both rapid and profound. SubAB favors cleavage of the newly synthesized immunoglobulin heavy chain-binding protein (BiP) to yield a C-terminal fragment that contains BiP's substrate-binding domain. In the absence of its regulatory nucleotide-binding domain, the SubAB-cleaved C-terminal BiP fragment remains tightly bound to newly synthesized immunoglobulin light chains, resulting in retention of light chains in the endoplasmic reticulum (ER). Immunoglobulins are thus detained in the ER, making impossible the secretion of antibodies by SubAB-treated B cells. The inhibitory effect of SubAB is highly specific for antibody secretion, because other secretory proteins such as IL-6 are released normally from SubAB-treated B cells. Although SubAB also causes BiP cleavage in HepG2 hepatoma cells, (glyco)protein secretion continues unabated in SubAB-exposed HepG2 cells. This specific block in antibody secretion is a novel means of immune evasion for STEC. The differential cleavage of newly synthesized versus "aged" BiP by SubAB in the ER provides insight into the architecture of the ER compartments involved.
authors.affiliation: Whitehead Institute for Biomedical Research, Cambridge, MA 02142, USA.
authors.forename: Chih-Chi Andrew
authors.initials: CC
authors.lastname: Hu
authors.forename: Stephanie K
authors.initials: SK
authors.lastname: Dougan
authors.forename: Sebastian Virreira
authors.initials: SV
authors.lastname: Winter
authors.forename: Adrienne W
authors.initials: AW
authors.lastname: Paton
authors.forename: James C
authors.initials: JC
authors.lastname: Paton
authors.forename: Hidde L
authors.initials: HL
authors.lastname: Ploegh
mesh_terms: D000818:Animals; D000906:Antibodies / Q000276:immunology*; D001402:B-Lymphocytes / Q000187:drug effects* / Q000276:immunology*; D002462:Cell Membrane / Q000187:drug effects; D004721:Endoplasmic Reticulum / Q000187:drug effects / Q000378:metabolism; D000091342:Endoplasmic Reticulum Chaperone BiP; D029968:Escherichia coli Proteins / Q000494:pharmacology*; D006360:Heat-Shock Proteins / Q000096:biosynthesis* / Q000737:chemistry; D015395:Histocompatibility Antigens Class I / Q000276:immunology; D007075:Immunoglobulin M / Q000276:immunology; D007145:Immunoglobulin kappa-Chains / Q000276:immunology; D015850:Interleukin-6 / Q000378:metabolism; D042541:Intracellular Space / Q000187:drug effects / Q000378:metabolism; D051379:Mice; D018448:Models, Immunological; D010446:Peptide Fragments / Q000378:metabolism; D017510:Protein Folding / Q000187:drug effects; D021381:Protein Transport / Q000187:drug effects; D013381:Subtilisins / Q000494:pharmacology*
chemical_list: D000906:Antibodies; D000091342:Endoplasmic Reticulum Chaperone BiP; D029968:Escherichia coli Proteins; D006360:Heat-Shock Proteins; D015395:Histocompatibility Antigens Class I; D007075:Immunoglobulin M; D007145:Immunoglobulin kappa-Chains; D015850:Interleukin-6; D010446:Peptide Fragments; D013381:Subtilisins; C527234:subtilase cytotoxin, E coli