Kaposi's sarcoma-associated herpesvirus latency-associated nuclear antigen dysregulates expression of MCL-1 by targeting FBW7

PLoS Pathog. 2021 Jan 20;17(1):e1009179. doi: 10.1371/journal.ppat.1009179. eCollection 2021 Jan.

Abstract

Primary effusion lymphoma (PEL) is an aggressive B cell lymphoma that is etiologically linked to Kaposi's sarcoma-associated herpesvirus (KSHV). Despite standard multi-chemotherapy treatment, PEL continues to cause high mortality. Thus, new strategies to control PEL are needed urgently. Here, we show that a phosphodegron motif within the KSHV protein, latency-associated nuclear antigen (LANA), specifically interacts with E3 ubiquitin ligase FBW7, thereby competitively inhibiting the binding of the anti-apoptotic protein MCL-1 to FBW7. Consequently, LANA-FBW7 interaction enhances the stability of MCL-1 by preventing its proteasome-mediated degradation, which inhibits caspase-3-mediated apoptosis in PEL cells. Importantly, MCL-1 inhibitors markedly suppress colony formation on soft agar and tumor growth of KSHV+PEL/BCBL-1 in a xenograft mouse model. These results strongly support the conclusion that high levels of MCL-1 expression enable the oncogenesis of PEL cells and thus, MCL-1 could be a potential drug target for KSHV-associated PEL. This work also unravels a mechanism by which an oncogenic virus perturbs a key component of the ubiquitination pathway to induce tumorigenesis.

Publication types

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

MeSH terms

  • Amino Acid Sequence
  • Animals
  • Antigens, Viral / genetics
  • Antigens, Viral / metabolism*
  • Apoptosis
  • Cell Proliferation
  • F-Box-WD Repeat-Containing Protein 7 / genetics
  • F-Box-WD Repeat-Containing Protein 7 / metabolism*
  • Female
  • Herpesvirus 8, Human / physiology*
  • Humans
  • Lymphoma, Primary Effusion / genetics
  • Lymphoma, Primary Effusion / metabolism
  • Lymphoma, Primary Effusion / pathology
  • Lymphoma, Primary Effusion / virology*
  • Mice
  • Mice, Inbred NOD
  • Mice, SCID
  • Myeloid Cell Leukemia Sequence 1 Protein / genetics
  • Myeloid Cell Leukemia Sequence 1 Protein / metabolism*
  • Nuclear Proteins / genetics
  • Nuclear Proteins / metabolism*
  • Phosphorylation
  • Sarcoma, Kaposi / genetics
  • Sarcoma, Kaposi / metabolism
  • Sarcoma, Kaposi / pathology
  • Sarcoma, Kaposi / virology*
  • Tumor Cells, Cultured
  • Ubiquitination
  • Xenograft Model Antitumor Assays

Substances

  • Antigens, Viral
  • F-Box-WD Repeat-Containing Protein 7
  • FBXW7 protein, human
  • MCL1 protein, human
  • Myeloid Cell Leukemia Sequence 1 Protein
  • Nuclear Proteins
  • latency-associated nuclear antigen