On the function of the interferon-inducible p53 target gene TRIM22

University dissertation from Division of Haematology and Transfusion Medicine

Abstract: The interferon-inducible p53-target gene TRIM22 (Staf50) is a member of the TRIM (TRIpartite Motif) family. The TRIM family is a family of RING (Really Interesting New Gene) proteins, defined through a tripartite motif, containing a RING-domain, one or two B-boxes and a Coiled-coil-domain. The TRIM proteins are involved in diverse biological functions, such as apoptosis, cell-cycle- progression and viral defence. Interferons (IFNs) are pleiotropic cytokines with antiviral, anti-proliferative, proapoptotic and immunmodulatory functions. Similar to TRIM22, many TRIM proteins are upregulated in response to IFNs, and many are involved in defence towards viruses, including TRIM22. TRIM22 has been shown to restrict HIV-1, hepatitis B and encephalomyocarditis virus. p53 is probably one of the most important tumour suppressor genes, and is positioned in the centre of signalling pathways that prevent proliferation and survival of potentially malignant cells. So far only TRIM22 and TRIM19 (PML) have been shown to be upregulated in response to p53, but recently several TRIM proteins have been shown to interact with and regulate p53. In my thesis, I have characterised the subcellular localisation and the functions of TRIM22. In paper I I show that endogenous TRIM22 localises to both the nucleus and cytoplasm. Furthermore, TRIM22 colocalises with the centrosomes irrespective of cell-cycle-phase, and with the endoplasmatic reticulum in primary cells and in cell-lines. In paper II I show that overexpressed TRIM22 suppresses translation through direct or indirect interaction with the translation initiation factor eIF4E and disruption of the eIF4F-complex. My data suggest that TRIM22 may suppress translation of a subset of mRNAs, particularly dependent on eIF4F for their translation. In paper III I show overexpressed TRIM22 to induce either repressed proliferation or cell-death depending on cellular context. Taken together, my data show cell-death-inducing, antiproliferative, translation-inhibitory effects of TRIM22, consistent with a role both as a tumour suppressor downstream of p53-signalling, and with immunomodulation downstream of IFNs. However, many new questions have been raised and further studies are warranted to understand all aspects of the function of TRIM22.