蛋白酶 MALT1 在潜伏膜蛋白 1 和 2 介导的 EBV B 细胞转化中的作用

Epstein-Barr virus (EBV) is a human herpesvirus that causes a variety of hematological malignancies, in particular B-, T- and NK-cell lymphomas. Latency proteins of the virus contribute to lymphomagenesis by activating the transcription factor NF- B, however, the molecular mechanism underlying EBV-driven NF- B activation remains incompletely understood.

Here we show that EBV latent membrane proteins LMP1 and LMP2A or LMP2B synergize to activate the protease MALT1, a key driver of NF- B-mediated lymphocyte proliferation. EBV-positive B-cell lines co-expressing LMP1 and LMP2 proteins exhibited constitutive MALT1 activity, and treatment with a MALT1 inhibitor or silencing of latent membrane protein-1 (LMP1) or LMP2 impaired MALT1-dependent substrate cleavage.

LMP1 physically interacted with the MALT1-binding partner BCL10, while LMP2A and LMP2B interacted with MALT1. LMP1 also colocalized with LMP2 in dotted structures, suggesting that LMP1 and LMP2 synergize via the coordinated formation of LMP-BCL10-MALT1 (LBM) complexes.

Finally, MALT1 protease inhibition led to reduced expression of a set of NF- B-driven genes, and reduced tumor growth in an EBV-positive lymphoma xenograft model.

These findings establish a key role for the protease MALT1 in LMP1/2-mediated, NF- B-driven cellular transformation and provide a rationale for inhibiting MALT1 to treat EBV-positive B-cell lymphomas that co-express LMP1 and LMP2.