Alpha-Actinin-4 Supports B Cell Survival by Limiting Lateral BCR Mobility

by Saed Alsouri
Doctoral thesis
Date of Examination:2023-09-13
Date of issue:2023-10-17
Advisor:Prof. Dr. Jürgen Wienands
Referee:Prof. Dr. Jürgen Wienands
Referee:Prof. Dr. Matthias Dobbelstein
Referee:Prof. Dr. Markus Bohnsack
Referee:Prof. Dr. Holger Bastians
Referee:Prof. Dr. Holger Reichardt
Referee:Prof. Dr. Ralph Kehlenbach
Persistent Address: http://dx.doi.org/10.53846/goediss-10139

 

 

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Abstract

English

The B cell antigen receptor (BCR) is involved in many cellular processes that define B cell fate. Once engaged by a cognate antigen, the BCR initiates a series of signaling cascades that drive B cell activation, proliferation, and differentiation. However, even in the absence of antigen binding, the BCR emits a steady-state signal with a very low intensity referred to as antigen-independent BCR signaling or tonic BCR signaling, which is essential for mature B cell survival, since the genetic ablation of BCR expression leads to rapid cell death. A substantial subset of Burkitt’s lymphoma (BL), which is an aggressive form of non-Hodgkin B cell lymphoma, exploits tonic BCR signals for their survival. While large parts of the tonic BCR signal network in BL cells have been identified by mass spectrometry, the details of these signals in the physiological context remain unclear. Among the identified tonic BCR effectors are many cytoskeleton regulators including the F-Actin cross-linking protein alpha-Actinin-4 (ACTN4), which has been shown to be crucial for BL cell survival. The aim of this thesis was, therefore, to functionally characterize the relevance of ACTN4 for tonic BCR survival signals in human primary B cells. For this purpose, a cellular model was established that enables the investigation of signal transduction in a primary-like B cell state. Based on generated cell lines with abrogated ACTN4 expression as well as primary human B cells, I could show that ACTN4 contributes to resting mature B cell survival. This effect correlates with an ACTN4-dependent stabilization of the cortical F-Actin, thereby confining the lateral BCR mobility as revealed by single particle tracking microscopy. Analysis of critical BCR effector proteins revealed that less mobile BCRs more efficiently transduce tonic survival signals. This function is ACTN4-specific, since alpha-Actinin-1 (ACTN1), which is also expressed in B cells, is not involved in BCR survival signals. Hence, this study characterizes ACTN4 as a tonic BCR effector protein in resting mature B cells and implies that the tight regulation of cortical F-Actin dynamics in B cells is critical to control tonic BCR survival signals.
Keywords: Tonic BCR signaling; Actinin; cortical cytoskeleton; BCR diffusion
 
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