TRIP13 modulates protein deubiquitination and accelerates tumor development and progression of B cell malignancies

J Clin Invest. 2021 Jul 15;131(14):e146893. doi: 10.1172/JCI146893.


Multiple myeloma (MM), a terminally differentiated B cell malignancy, remains difficult to cure. Understanding the molecular mechanisms underlying the progression of MM may identify therapeutic targets and lead to a fundamental shift in treatment of the disease. Deubiquitination, like ubiquitination, is a highly regulated process, implicated in almost every cellular process. Multiple deubiquitinating enzymes (DUBs) have been identified, but their regulation is poorly defined. Here, we determined that TRIP13 increases cellular deubiquitination. Overexpression of TRIP13 in mice and cultured cells resulted in excess cellular deubiquitination by enhancing the association of the DUB USP7 with its substrates. We show that TRIP13 is an oncogenic protein because it accelerates B cell tumor development in transgenic mice. TRIP13-induced resistance to proteasome inhibition can be overcome by a USP7 inhibitor in vitro and in vivo. These findings suggest that TRIP13 expression plays a critical role in B cell lymphoma and MM by regulating deubiquitination of critical oncogenic (NEK2) and tumor suppressor (PTEN, p53) proteins. High TRIP13 identifies a high-risk patient group amenable to adjuvant anti-USP7 therapy.

Keywords: Drug therapy; Hematology; Oncogenes; Ubiquitin-proteosome system.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, Non-P.H.S.

MeSH terms

  • ATPases Associated with Diverse Cellular Activities / genetics
  • ATPases Associated with Diverse Cellular Activities / metabolism*
  • Animals
  • B-Lymphocytes / metabolism*
  • Carcinogenesis / genetics
  • Carcinogenesis / metabolism*
  • Cell Cycle Proteins / genetics
  • Cell Cycle Proteins / metabolism*
  • Lymphoma, B-Cell / genetics
  • Lymphoma, B-Cell / metabolism*
  • Mice
  • Mice, Transgenic
  • Multiple Myeloma / genetics
  • Multiple Myeloma / metabolism*
  • Neoplasm Proteins / genetics
  • Neoplasm Proteins / metabolism*
  • Ubiquitination*


  • Cell Cycle Proteins
  • Neoplasm Proteins
  • ATPases Associated with Diverse Cellular Activities
  • Trip13 protein, mouse