Managing and exploiting stress in the antibody factory

Abstract 

Like us, our cells have evolved strategies to cope with, and sometimes utilize, stress. Molecular analyses of plasma cell biogenesis, lifestyle and death suggest that protein synthesis-dependent stress is utilised to integrate differentiation, function and lifespan control. Plasma cells are short-lived professional secretory cells, each of them capable of releasing several thousands antibodies per second. Their differentiation from B lymphocytes entails the spectacular enlargement of the endoplasmic reticulum (ER), finalized to sustain massive Ig production. Nonetheless, symptoms of ER stress are evident, and the UPR-related transcription factor XBP-1 is essential for differentiation. Surprisingly, the development of such an efficient factory is matched by a decrease in proteasomes. The unbalanced load/capacity ratio leads to accumulation of polyubiquitinated molecules and predisposes plasma cells to apoptosis. Exuberant antibody secretion imposes considerable stress on metabolic and redox homeostasis. Collectively, these stressful conditions may link plasma cell death to antibody production, providing a molecular counter for secreted molecules, as well as an explanation for the peculiar sensitivity of myeloma cells towards proteasome inhibitors.

Abbreviations: DRiPs, defective ribosomal products, ER, endoplasmic reticulum, ERAD, ER associated degradation, Ig, immunoglobulin, MM, multiple myeloma, PDI, protein disulfide isomerase, PI, proteasome inhibitors, RDP, rapidly degraded polypeptides, ROS, reactive oxygen species, UPR, unfolded protein response

Keywords: Antibody secretion, Differentiation, Plasma cell, Protein synthesis and degradation, Proteasomes, Redox, Stress