Germinal centre protein HGAL promotes lymphoid hyperplasia and amyloidosis via BCR-mediated Syk activation.

Abstract

The human germinal centre-associated lymphoma gene is specifically expressed in germinal centre B-lymphocytes and germinal centre-derived B-cell lymphomas, but its function is largely unknown. Here we demonstrate that human germinal centre-associated lymphoma directly binds to Syk in B cells, increases its kinase activity on B-cell receptor stimulation and leads to enhanced activation of Syk downstream effectors. To further investigate these findings in vivo, human germinal centre-associated lymphoma transgenic mice were generated. Starting from 12 months of age these mice developed polyclonal B-cell lymphoid hyperplasia, hypergammaglobulinemia and systemic reactive amyloid A (AA) amyloidosis, leading to shortened survival. The lymphoid hyperplasia in the human germinal centre-associated lymphoma transgenic mice are likely attributable to enhanced B-cell receptor signalling as shown by increased Syk phosphorylation, ex vivo B-cell proliferation and increased RhoA activation. Overall, our study shows for the first time that the germinal centre protein human germinal centre-associated lymphoma regulates B-cell receptor signalling in B-lymphocytes which, without appropriate control, may lead to B-cell lymphoproliferation.

• Authors: Isabel Romero-Camarero, Xiaoyu Jiang, Yasodha Natkunam, Xiaoqing Lu, Carolina Vicente-Dueñas, Ines Gonzalez-Herrero, Teresa Flores, Juan Luis Garcia, George McNamara, Christian Kunder, Shuchun Zhao, Victor Segura, Lorena Fontan, Jose A Martínez-Climent, Francisco Javier García-Criado, Jason D Theis, Ahmet Dogan, Elena Campos-Sánchez, Michael R Green, Ash A Alizadeh, Cesar Cobaleda, Isidro Sánchez-García, Izidore S Lossos
• Journal: Nature communications (Nat Commun) Vol. 4 Pg. 1338 ( 2013) ISSN: 2041-1723 [Electronic] England
• PMID: 23299888 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)

Chemical References

• Antigens, Ly
• Cell Extracts
• GCSAM protein, human
• Intracellular Signaling Peptides and Proteins
• Ly6a protein, mouse
• Membrane Proteins
• Microfilament Proteins
• Neoplasm Proteins
• RNA, Small Interfering
• Receptors, Antigen, B-Cell
• Saa2 protein, mouse
• Serum Amyloid A Protein
• Protein-Tyrosine Kinases
• SYK protein, human
• Syk Kinase
• Syk protein, mouse
• rhoA GTP-Binding Protein

Topics

• Amino Acid Sequence
• Amyloidosis (complications, pathology)
• Animals
• Antigens, Ly (metabolism)
• Cell Extracts
• Disease Models, Animal
• Enzyme Activation
• Germinal Center (metabolism, pathology)
• Humans
• Hypergammaglobulinemia (pathology)
• Hyperplasia
• Intracellular Signaling Peptides and Proteins (metabolism)
• Intracellular Space (metabolism)
• Kaplan-Meier Estimate
• Lymphoma, B-Cell (complications, enzymology, pathology)
• Membrane Proteins (metabolism)
• Mice
• Microfilament Proteins
• Molecular Sequence Data
• Neoplasm Proteins (metabolism)
• Protein Binding
• Protein-Tyrosine Kinases (metabolism)
• RNA, Small Interfering (metabolism)
• Receptors, Antigen, B-Cell (metabolism)
• Serum Amyloid A Protein (chemistry, metabolism)
• Signal Transduction
• Spleen (metabolism, pathology)
• Syk Kinase
• Transcriptome (genetics)
• rhoA GTP-Binding Protein (metabolism)