Updated project metadata. The E3 ubiquitin ligase Itch regulates antibody levels and prevents autoimmune disease in humans and mice, yet how Itch regulates B cell fate or function is unknown. We now show that Itch directly limits B cell activity. Using LC-MSMS, we profiled and compared the whole cell proteomes of Itch deficient and Itch sufficient CpG-stimulated B cells. B cells lacking Itch exhibited increased levels of mTORC1 targets and E2F transcription factor targets. These results support a novel role for Itch in limiting B cell metabolism and proliferation.