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Defective immune responses in mice lacking LUBAC-mediated linear ubiquitination in B cells
Yoshiteru Sasaki1, Soichi Sano, Masaki Nakahara
1Department of Molecular and Cellular Physiology, Graduate School of Medicine, Kyoto University, Kyoto, Japan.
Insights
The linear ubiquitin chain assembly complex (LUBAC) is vital for B-cell development and antibody production. Ablating LUBAC
Area of Science:
- Immunology
- Molecular Biology
- Cell Biology
Background:
- The linear ubiquitin chain assembly complex (LUBAC) is a key regulator of cellular signaling pathways.
- Canonical NF-κB pathway activation is critical for B-cell development, function, and immune responses.
- LUBAC's role in B-cell specific signaling, particularly via TNF receptor superfamily, requires further elucidation.
Purpose of the Study:
- To investigate the specific role of LUBAC-mediated linear polyubiquitination in B-cell development and function.
- To determine the impact of ablating LUBAC's linear polyubiquitination activity on B-cell signaling pathways.
- To assess the consequences for antibody production and B-cell subset development.
Main Methods:
- Generation of a conditional knockout mouse model (B-HOIP(Δlinear)) with ablated LUBAC linear polyubiquitination specifically in B cells.
- Analysis of canonical NF-κB and ERK pathway activation in response to CD40, TACI, and B-cell receptor (BCR) stimulation.
- Evaluation of B-cell subset populations (e.g., B1 cells) and antibody responses to various antigens.
Main Results:
- Impaired canonical NF-κB and ERK activation in B cells from B-HOIP(Δlinear) mice upon stimulation via CD40 and TACI, linked to defective IKK complex activation.
- Unaffected NF-κB and ERK activation via B-cell receptor (BCR) signaling.
- Significant impairment in B1-cell development and antibody responses to thymus-dependent and thymus-independent II antigens in B-HOIP(Δlinear) mice.
Conclusions:
- LUBAC-mediated linear polyubiquitination is essential for B-cell development and antibody production.
- This essential role is mediated through TNF receptor superfamily-induced canonical NF-κB and ERK activation, not BCR signaling.
- LUBAC is a critical component for adaptive immunity, influencing B-cell homeostasis and effective humoral responses.
Abstract:
The linear ubiquitin chain assembly complex (LUBAC) plays a crucial role in activating the canonical NF-κB pathway, which is important for B-cell development and function. Here, we describe a mouse model (B-HOIP(Δlinear)) in which the linear polyubiquitination activity of LUBAC is specifically ablated in B cells. Canonical NF-κB and ERK activation, mediated by the tumour necrosis factor (TNF) receptor superfamily receptors CD40 and TACI, was impaired in B cells from B-HOIP(Δlinear) mice due to defective activation of the IKK complex; however, B-cell receptor (BCR)-mediated activation of the NF-κB and ERK pathways was unaffected. B-HOIP(Δlinear) mice show impaired B1-cell development and defective antibody responses to thymus-dependent and thymus-independent II antigens. Taken together, these data suggest that LUBAC-mediated linear polyubiquitination is essential for B-cell development and activation, possibly via canonical NF-κB and ERK activation induced by the TNF receptor superfamily, but not by the BCR.
