TRIM proteins in blood cancers

Abstract

Post-translational modification of proteins with ubiquitin plays a central role in regulating numerous cellular processes. E3 ligases determine the specificity of ubiquitination by mediating the transfer of ubiquitin to substrate proteins. The family of tripartite motif (TRIM) proteins make up one of the largest subfamilies of E3 ligases. Accumulating evidence suggests that dysregulation of TRIM proteins is associated with a variety of diseases. In this review we focus on the involvement of TRIM proteins in blood cancers.

Keywords: E3 ligase; Leukaemia; Lymphoma; Multiple myeloma; TRIM proteins; Ubiquitin.

Fig. 1

Structural classification of tripartite motif (TRIM) family proteins. The majority of TRIM proteins contain an N-terminal RING domain, one or two B-box domains (B1, B2) and a coiled-coil domain (CC) and are classified into 11 subfamilies (C-I – C-XI) based on a variable C-terminal domain; there is an additional unclassified group lacking a RING domain. Some family members lack one or more domain as denoted in brackets and by a dashed outline. TRIMs included in this review are in bold. Abbreviations: ACID – acid-rich region, ARF – ADP-ribosylation factor family domain, BROMO – bromodomain, COS – cos-box, FIL – filamin-type I G domain, FN3 – fibronectin type III repeat, MATH – meprin and TRAF-homology domain, NHL – NCL1, HT2A and LIN41 domain, PHD - PHD domain, PRY – PRY domain, SPRY – SPRY domain, TM – transmembrane region

Fig. 2

TRIM19/PML exerts cell type dependent effects on blood cancers. In acute promyelocytic leukaemia (APL), B cell acute lymphoblastic leukaemia (B-ALL) and non-Hodgkin’s lymphoma (NHL), the tumour suppressive activity of PML is lost. The majority of patients with APL harbour the t(15;17) translocation resulting in a promyelocytic leukaemia – retinoic acid receptor α (PML-RARα) gene and protein. This disrupts the normal function of both proteins leading to impaired PML-nuclear bodies (PML-NB) formation and a block in differentiation. In some cases of B-ALL, PML is found translocated to the transcription factor paired box 5 (PAX5), again disrupting the formation of PML-NB and leading to decreased differentiation. In NHL reduced protein expression of PML is seen due to increased E6AP-mediated proteasomal degradation of PML. Conversely, PML is seen to play an oncogenic role in chronic myeloid leukaemia (CML), where it has been found to be important for self-renewal and quiescence in leukaemic stem cells

Fig. 3

The dual role of TRIM33 in the regulation of blood cancers. In chronic myelomonocytic leukaemia (CMML) TRIM33 is epigenetically silenced through increased methylation of its promoter in approximately a third of patients, leading to loss of tumour suppressor activity. Conversely, TRIM33 has been found to be essential for the survival of B cell acute lymphoblastic leukaemia (B-ALL) cells by blocking enhancer mediated activation of the pro-apoptotic gene BIM