Autophagy, the cellular process of recycling and degrading damaged components or organelles, plays a vital role in various biological systems. In the immune system, it’s particularly involved in processes like B cell self-renewal and the survival of memory and plasma B cells. However, the impact of boosting autophagy in B cells remains somewhat mysterious.
A recent study led by researchers identified a shorter isoform of the protein Rubicon called RUBCN100. This isoform was found to enhance autophagy in B cells (Figure 1). Notably, mice lacking the longer isoform, RUBCN130, generated more memory B cells, a process dependent on autophagy. These findings significantly contribute to our understanding of Rubicon’s role in autophagy.
Rubicon is a protein known to inhibit autophagy and has far-reaching effects on various health conditions, including fatty liver, kidney fibrosis, brain α-synuclein accumulation, systemic fat atrophy, osteoporosis, and myocardial ischemia/reperfusion injury. However, a deficiency in RUBCN can also lead to metabolic syndrome and reduced Sertoli cell function in mice.
In the study, the scientists pinpointed RUBCN100, which enhances autophagy in B cells. Mice lacking RUBCN130 or expressing RUBCN100 showed increased autophagy in B cells. This, in turn, led to the generation of more memory B cells and suppressed the differentiation of plasmablasts, a type of antibody-producing cell. Enhanced autophagy shifted the fate of B cell differentiation without affecting the formation or survival of germinal centers, which are crucial for the production of high-affinity antibodies.
The researchers discovered that the interaction between the two RUBCN isoforms, RUBCN130 and RUBCN100, is a key regulator of autophagy. Striking the right balance between these isoforms is crucial for maintaining cellular equilibrium and controlling autophagy and mTORC1 activity. RUBCN deficiency and pharmacological enhancement of autophagy can lead to a significant increase in memory B cell generation.
This revelation of RUBCN100 not only reconciles conflicting findings about the functions of RUBCN but also provides insights into the regulation of B cell memory. These findings have the potential to open new avenues for research and therapeutic interventions in conditions related to immune memory and autophagy.
Journal article: Chao-Yuan, CY., et al, 2023. Opposing roles of RUBCN isoforms in autophagy and memory B cell generation, Science Signaling.
Summary by Stefan Botha