Rousseaux MW, de Haro M, Lasagna-Reeves CA, De Maio A, Park J, Jafar-Nejad P, Al-Ramahi I, Sharma A, See L, Lu N, Vilanova-Velez L, Klisch TJ, Westbrook TF, Troncoso JC, Botas J, Zoghbi HY. TRIM28 regulates the nuclear accumulation and toxicity of both alpha-synuclein and tau. Elife. 2016 Oct 25;5 PubMed.
Recommends
Please login to recommend the paper.
Comments
University of Cambridge
This is a very interesting paper centered on TRIM28, which was found by phenotypic screens to stabilize tau and α-synuclein and promote their nuclear localization. TRIM28 is a member of the TRIM family, of which there are ~100 in the human genome. We have recently published findings on the intracellular clearance of tau-antibody complexes by another member of this family, TRIM21 (see Jan 2017 news). Are the findings related? TRIM proteins share a common core domain organization: the so-called tripartite motif, which consists of a RING E3 ligase domain, one or more B-Box domains and a Coiled-Coil, which promotes homo-dimerization. Most TRIM proteins have one or more additional C-terminal domains, which are often responsible for heterotypic protein-protein interactions. TRIM21 possesses a PRYSPRY domain at its C-terminus, which we have demonstrated to have sub-nanomolar affinity for antibody Fc domain. TRIM21 is therefore recruited to intracellular antibody-bound particles and mediates their proteasomal destruction over the course of minutes. Thus, TRIM21 has a specialized role in defending the cytosol against antibody-labeled invading particles, including non-enveloped viruses. We showed this activity also extends to tau fibrils during in vitro seeding reactions. In contrast, TRIM28 possesses C-terminal HP1-binding, PHD and Bromo domains, which are known to promote interactions with transcriptional regulators and heterochromatin. Accordingly, TRIM28 is a key regulator of transcriptional activity. However, in this study by Rousseaux et al., the role of TRIM28 in stabilization of tau and α-synuclein appeared to be distinct from its role as a transcriptional regulator. Rather, stabilization relied on a RING-dependent activity at the protein level. A key question is whether TRIM28 binds directly to tau and α-synuclein and which of its domains are responsible for any such interactions. In summary, the physiological roles of TRIM21 and TRIM28 are highly divergent and the two papers do not describe a common process. However, the papers serve as a demonstration that the functional diversity of TRIM proteins is large and they may play important roles in numerous cellular functions, including in protein homeostasis, anti-microbial defense, and neurodegeneration.
Make a Comment
To make a comment you must login or register.