Plasma cell subsets vary in their lifespans and ability to sustain humoral immunity. We conducted a genome-wide CRISPR-Cas9 screen in a myeloma cell line for factors that promote surface expression of CD98, a marker of longevity in primary mouse plasma cells. A large fraction of genes found to promote CD98 expression in this screen are involved in secretory and other vesicles, including many subunits of the V-type ATPase complex. Chemical inhibition or genetic ablation of V-type ATPases in myeloma cells reduced antibody secretion. Primary mouse and human long-lived plasma cells had greater numbers of acidified vesicles than did their short-lived counterparts, and this correlated with increased secretory capacity of IgM, IgG, and IgA. The screen also identified PI4KB, which promoted acidified vesicle numbers and secretory capacity, and DDX3X, an ATP-dependent RNA helicase, the deletion of which reduced immunoglobulin secretion independently of vesicular acidification. Finally, we report a plasma-cell intrinsic function of the signaling adapter MYD88 in both antibody secretion and plasma cell survival