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.

The let-7 microRNA Directs Vulval Development through a Single Target

“…Thus, it will be interesting to determine in future research whether LIN-41 directs vulval integrity by contributing directly to structural integrity of the vulva, or whether its preferred mode of action involves posttranscriptional and/or posttranslational regulation of specific target genes (Ecsedi and Großhans, 2013). Indeed, one may speculate that it is the diverse molecular activities of LIN-41 that provide the versatility of the let-7/LIN-41 regulatory module, which regulates tissue integrity in the vulva (this study), but self-renewal and differentiation in the C. elegans epidermis as well as many other contexts (Ecsedi and Großhans, 2013;Bü ssing et al, 2008).…”

“…Specifically, C. elegans let-7 promotes differentiation and blocks proliferation of the epidermal seam cells at the transition from fourth larval (L4) to the adult stage (Reinhart et al, 2000;Slack et al, 2000). It does so, at least in part, by regulation of the TRIM-NHL (tripartite motif-NCL-1, HT2A2, and LIN-41 domain) protein LIN-41/ TRIM71, itself a key regulator of pluripotency and proliferation (reviewed in Ecsedi and Großhans, 2013). Genetic interactions further suggest that let-7 functions through the transcription factor LIN-29, which may itself be a direct target of LIN-41 .…”

Alteration of miRNA activity via context-specific modifications of Argonaute proteins

“…Previously, the ubiquitin ligase mLin-41 was reported to modify mAgo2 and inhibit its accumulation in mES cells [33]. Notably, C. elegans lin-41 emerged as one of the key targets of the let-7 miRNA during larval-to-adult transition [34], and this miRNA-target interaction is among the few conserved from invertebrates to vertebrates [35]. Although subsequent studies have not confirmed a functional impact of mLin-41 ubiquitination of Ago2, the association of these factors is reproducible [36–38].…”

LEP-2/Makorin regulates LIN-28 stability to promote the juvenile-to-adult transition in Caenorhabditis elegans

“…When LIN-28 is downregulated, mature let-7 miRNA is produced, directing cells toward differentiated/adult fates (Copley et al, 2013;Hayes and Ruvkun, 2006;Rybak et al, 2008;Thornton and Gregory, 2012;Tsialikas and Romer-Seibert, 2015;Yu et al, 2007) by inhibiting the translation of primarily lin-41 and other target mRNAs (Ecsedi and Grosshans, 2013;Long et al, 2007;Slack et al, 2000;Vella et al, 2004a,b). homologs are proposed to silence the translation of target mRNAs (Ecsedi and Grosshans, 2013;Ecsedi et al, 2015;Loedige et al, 2013;Sonoda and Wharton, 2001;Vella et al, 2004a,b) that otherwise promote an undifferentiated/juvenile state (Chang et al, 2012;Ecsedi and Grosshans, 2013;Rybak et al, 2009).…”