title: HAX1 deletion impairs BCR internalization and leads to delayed BCR-mediated apoptosis.
abstract: Deletion of HAX1 in mice causes a severe reduction in the numbers of lymphocytes in the bone marrow and in the spleen. Additionally, B220(+) B progenitor cells in the bone marrow are reduced, suggesting an important function of HAX1 in B cell development. HAX1 is thought to play a protective role in apoptotic processes; therefore, we investigated the role of HAX1 in bone marrow B progenitor cells and splenic B cells. We did not observe an effect on the survival of Hax1(-/-) bone marrow cells but detected enhanced survival of splenic Hax1(-/-) B cells upon in vitro starvation/growth-factor withdrawal. To explain this apparent inconsistency with previous reports of HAX1 function, we also studied the B cell receptor (BCR)-induced apoptosis of IgM-stimulated splenic naïve B cells and found that apoptosis decreased in these cells. We further found impaired internalization of the BCR from Hax1(-/-) splenic B cells after IgM crosslinking; this impaired internalization may result in decreased BCR signaling and, consequently, decreased BCR-mediated apoptosis. We measured HAX1 binding to the cytoplasmic domains of different Ig subtypes and identified KVKWI(V)F as the putative binding motif for HAX1 within the cytoplasmic domains. Because this motif can be found in almost all Ig subtypes, it is likely that HAX1 plays a general role in BCR-mediated internalization events and BCR-mediated apoptosis.
authors: Department of Molecular Biology, University of Salzburg, Salzburg, Austria.
authors: Susanne
authors: S
authors: Wolkerstorfer
authors: Department of Molecular Biology, University of Salzburg, Salzburg, Austria.
authors: Elisabeth
authors: E
authors: Schwaiger
authors: Department of Cell Biology, University of Salzburg, Salzburg, Austria.
authors: Mark
authors: M
authors: Rinnerthaler
authors: Department of Molecular Biology, University of Salzburg, Salzburg, Austria.|Department of Dermatology, University of California San Francisco, CA, USA.|Department of Dermatology, Division of Molecular Dermatology and EB House Austria, Paracelsus Medical University, Salzburg, Austria.
authors: Iris
authors: I
authors: Karina Gratz
authors: Department of Molecular Biology, University of Salzburg, Salzburg, Austria.
authors: Thomas
authors: T
authors: Zoegg
authors: Department of Molecular Biology, University of Salzburg, Salzburg, Austria.
authors: Hans
authors: H
authors: Brandstetter
authors: Department of Molecular Biology, University of Salzburg, Salzburg, Austria.
authors: Gertrude
authors: G
authors: Achatz-Straussberger
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000187:drug effects; D001402:B-Lymphocytes / Q000187:drug effects / Q000378:metabolism; D001854:Bone Marrow Cells / Q000187:drug effects / Q000378:metabolism; D002452:Cell Count; D045744:Cell Line, Tumor; D002470:Cell Survival / Q000187:drug effects; D004705:Endocytosis / Q000187:drug effects; D017353:Gene Deletion; D007136:Immunoglobulins / Q000737:chemistry / Q000378:metabolism; D036341:Intercellular Signaling Peptides and Proteins / Q000494:pharmacology; D047908:Intracellular Signaling Peptides and Proteins; D007700:Kinetics; D018655:Lymphocyte Count; D008214:Lymphocytes / Q000187:drug effects / Q000378:metabolism; D008807:Mice, Inbred BALB C; D011485:Protein Binding / Q000187:drug effects; D000072417:Protein Domains; D011506:Proteins / Q000378:metabolism*; D011947:Receptors, Antigen, B-Cell / Q000378:metabolism*; D013154:Spleen / Q000166:cytology
chemical_list: C491295:Hs1bp1 protein, mouse; D007136:Immunoglobulins; D036341:Intercellular Signaling Peptides and Proteins; D047908:Intracellular Signaling Peptides and Proteins; D011506:Proteins; D011947:Receptors, Antigen, B-Cell