LAUSR

Antibody-secreting plasma cells (ASCs) protect from infection by secreting pathogen-specific antibodies (Abs). As Abs have a typical half-life of days to weeks, underpinning longterm humoral immunity is the requirement for longevity of ASCs and their continual production of Abs. Research over the last 25 years has uncovered many of the soluble and membrane-bound factors important for ASC differentiation and identity; however, the molecular mechanisms that facilitate ASC persistence are only now beginning to be unraveled. In a recent article, Bonaud and colleagues took the next step in this process, reporting a novel role for the protein Sec22b in regulating ASC function, organelle morphology and accumulation. Using elegant techniques such as DropMap to measure single cell Ab production rates, they showed that Sec22b plays a unique and nonredundant role in ASC biology with implications for targeting of pathogenic ASCs in disease contexts (Figure 1). Sec22b is a soluble N-ethylmaleimide–sensitive factor attachment protein receptor (SNARE) protein. SNAREs represent a broad family of proteins whose primary function is to mediate fusion of vesicles with membranes such as the endoplasmic reticulum (ER), Golgi network and mitochondria. As such, SNAREs are regulators of exocytosis, an important process for the secretion of high volumes of Abs, which also requires the unfolded protein response (UPR) to maintain ASC integrity. Sec22b has been shown to be key for bidirectional transport between the ER and Golgi. Sec22b is broadly expressed in B cells at all developmental stages but is upregulated transcriptionally and as a protein in both mouse and human ASCs. Because of its more than threefold upregulation in committed ASCs in comparison to B cells, Sec22b comprises one of the key “signature” genes that defines the ASC lineage. In their study, Bonaud and colleagues generated a B-cell-Sec22b knockout mouse strain (Mb1cre.Sec22b) to investigate the role of Sec22b in ASC biology. In contrast to the largely normal B-cell development observed in the Mb1cre.Sec22b mice, the authors found more than 10-fold reductions in total ASC numbers, 40–60-fold reduced basal Ab titers, and following immunization, a dearth of ASCs and serum antigen-specific Abs. In addition to showing reductions in ASC numbers, the authors used a microfluidics-based system for the real-time identification of Ab secretion from single cells, named DropMap, to show that in Sec22b-deficient ASCs generated in vitro, Ab secretion was reduced twofold to fourfold compared with wild-type ASCs. This means that the combined impact of a loss of ASCs and a reduction in their Abs production, together explain the loss of Abs from sera. This fits with the notion that Abs are secreted through constitutive exocytosis and are highly dependent on vesicle fusion. However, prolific Ab secretion is not a requirement for ASC survival, as evidenced by mice deficient in XBP1 (X-box binding protein 1), suggesting a role of Sec22b in ASC function beyond the simple secretion of Abs and death because of a break in this aspect of the vesicle fusion process. Upon differentiation, ASCs undergo significant expansion of the ER to facilitate a high degree of Ab production and secretion. Possibly causal to the Ab secretion deficits, Sec22b-deficient ASCs exhibited several remarkable phenotypes, including disrupted morphology of the ER and mitochondria; the ER was less expanded and displayed a highly irregular structure with dilated cisternae. Further, there was a decreased ER–mitochondria contact surface area and a dysfunctional hyperfused morphology of those mitochondria in the cells. Functionally, these defects were associated with compromised fitness, although it is not clear whether the ER and mitochondrial changes are a direct or indirect result of Sec22b deficiency. However, from the study it is clear that Sec22b plays a role in establishing ASC structure and function. Correspondence Marcus James Robinson, Immunology Department, Monash University, Level 6, Burnet Tower, 89 Commercial Road, Prahran, VIC, Australia. E-mail: [email protected]