LIN-41/TRIM71: emancipation of a miRNA target

Abstract

lin-41 (lineage variant 41)/TRIM71 (tripartite motif 71) is well known for being a conserved target of the let-7 (lethal 7) microRNA (miRNA), a regulatory relationship found in animals evolutionarily as distant as Caenorhabditis elegans and humans. It has thus been studied extensively as a model for miRNA-mediated gene silencing. In contrast, the developmental and molecular functions of LIN41 have historically received less attention. However, LIN41 proteins are now emerging as important regulators of cell proliferation and differentiation in stem and progenitor cells. Moreover, LIN41's functions appear to involve two distinct molecular activities; namely, protein ubiquitylation and post-transcriptional silencing of mRNAs. Thus, LIN41 is ready for a scientific life of its own.

Figure 1.

Domain architecture of LIN41 proteins from different species. The indicated domains were identified using SMART (http://smart.embl-heidelberg.de) and CDART (http://www.ncbi.nlm.nih.gov/Structure/lexington/lexington.cgi) algorithms. Domain sizes are approximately to scale. Note that two isoforms have been reported for C. elegans, LIN41a and LIN41B, which only differ by three amino acids (Slack et al. 2000).

Figure 2.

Proposed models of LIN41 function. (A) LIN41 ubiquitylates SHCBP1 to augment FGF signaling, increase proliferation rate, and inhibit premature differentiation in neural progenitor cells (J Chen et al. 2012). (B) LIN41 ubiquitylates AGO, inducing its degradation by the proteasome, leading to decreased miRNA activity (Rybak et al. 2009). (C) LIN41 induces degradation and translational inhibition of target mRNAs such as CDKN1a, promoting rapid proliferation of ES cells (Chang et al. 2012; Loedige et al. 2012). See the text for details.