Editors' ChoiceCell Biology

TRIMs for Autophagy

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Sci. Signal.  02 Sep 2014:
Vol. 7, Issue 341, pp. ec237
DOI: 10.1126/scisignal.2005850

Tripartite motif (TRIM) proteins function in diverse cellular processes, including growth, differentiation, and apoptosis. TRIMs can also act as pattern-recognition receptors (PRRs) to promote antiviral responses. Mandell et al. surveyed 67 human TRIM proteins and found that most also functioned in basal or induced nonselective (bulk) autophagy in HeLa cells, either promoting or inhibiting the formation of cytoplasmic puncta containing the autophagosomal marker LC3B. Further analysis of TRIM5α in HeLa and 293T cells revealed that this TRIM colocalized with LC3B, the autophagy receptor p62, and the serine-threonine kinase ULK1. In coimmunoprecipitation assays, TRIM5α interacted with several mammalian homologs of yeast Atg8 (mATG8s), the activated form of ULK1, and Beclin 1, all of which are required for autophagy. A complex containing TRIM5α, ULK1, and the form of Beclin 1 that was phosphorylated and activated by ULK1 also coimmunoprecipitated from 293T cells. Activation of ULK1 and its accumulation on nascent autophagosomes are essential early steps in autophagy, and knocking down TRIM5α reduced the accumulation of puncta containing activated ULK1. Overexpression of TRIM5α induced autophagy and triggered dissociation of Beclin 1 from its inhibitors Bcl-2 and TAB2. The authors mapped the regions of TRIM5α that mediated binding to p62, Beclin 1, and the mAtg8 GABARAP and proposed that TRIM5α stimulates autophagy by bringing together these components of the autophagy machinery. Several other TRIMs also interacted with mAtg8s, p62, ULK1, and Beclin 1, suggesting that other TRIMs may stimulate autophagy through analogous mechanisms.

TRIM5α binds to retroviral capsid proteins to mediate antiviral signaling, so the authors investigated whether TRIM5α targets the HIV-1 capsid protein p24 for autophagic degradation. In cultured rhesus macaque FRhK4 cells, targeting of p24 for autophagy required several autophagy proteins, including p62, Beclin1, and TRIM5α. Furthermore, mutating amino acid residues in the region of TRIM5α that mediated binding to the mATG8 GABARAP prevented autophagic degradation of p24 and reduced the TRIM5α-induced accumulation of puncta containing LC3B and activated ULK1. These findings suggest a model in which TRIM5α can act as a platform for formation of the autophagy machinery and target specific cargo to nascent autophagosomes for degradation.

M. A. Mandell, A. Jain, J. Arko-Mensah, S. Chauhan, T. Kimura, C. Dinkins, G. Silvestri, J. Münch , F. Kirchhoff, A. Simonsen, Y. Wei, B. Levine, T. Johansen, V. Deretic, TRIM proteins regulate autophagy and can target autophagic substrates by direct recognition. Dev. Cell 30, 394–409 (2014). [PubMed]