Ccr4-Not as a mediator of environmental signaling: a jack of all trades and master of all

Abstract

The cellular response to environmental exposures, such as nutrient shifts and various forms of stress, requires the integration of the signaling apparatus that senses these environmental changes with the downstream gene regulatory machinery. Delineating this molecular circuitry remains essential for understanding how organisms adapt to environmental flux, and it is critical for determining how dysregulation of these mechanisms causes disease. Ccr4-Not is a highly conserved regulatory complex that controls all aspects of the gene expression process. Recent studies in budding yeast have identified novel roles for Ccr4-Not as a key regulator of core nutrient signaling pathways that control cell growth and proliferation, including signaling through the mechanistic target of rapamycin complex 1 (TORC1) pathway. Herein, I will review the current evidence that implicate Ccr4-Not in nutrient signaling regulation, and I will discuss important unanswered questions that should help guide future efforts to delineate Ccr4-Not's role in linking environmental signaling with the gene regulatory machinery. Ccr4-Not is highly conserved throughout eukaryotes, and increasing evidence indicates it is dysregulated in a variety of diseases. Determining how Ccr4-Not regulates these signaling pathways in model organisms such as yeast will provide a guide for defining how it controls these processes in human cells.

Keywords: Ccr4-Not; Lysosome; Nutrient signaling; TORC1; Transcription; V-ATPase.

Figure 1.. Structural organization of the yeast Ccr4-Not complex.

A. Cryo-EM structure of the S. pombe Ccr4-Not complex (structure EMD-3232) downloaded from the Yorodumi PDB/EMDB/SASBDB browser (https://pdbj.org/emnavi/quick/php?id=emdb-3232). Note that this structure has the S. pombe specific Mmi subunit present which is not found in S. cerevisiae (Ukleja et al. 2016a). B. Illustration highlighting the relative distribution of the different S. cerevisiae Ccr4-Not subunits on the Not1 scaffolding subunit.

Figure 2.. Composition of the yeast and human Ccr4-Not complexes.

Orthologous sub-module specific subunits are color coded. Note that while yeast Not4 is a stable and stoichiometric Ccr4-Not subunit, human CNOT4 interactions are more dynamic and are mediated predominantly by the CNOT9 (Caf40) subunit (indicated by the arrow).

Figure 3.. Candidate model for Ccr4-Not mediated nutrient signaling.

Ccr4-Not acts upstream of the lysosomal V-ATPase to promote its assembly and/or stability, which is necessary for full TORC1 activation. Whether this is through direct regulation of the V-ATPase by Ccr4-Not mediate ubiquitination, or if it involves Ccr4-Not’s role as a chaperone compex, has yet to be determined. Because the V-ATPase also activates the Ras/PKA pathway, Ccr4-Not also may be required for full Ras/PKA signaling. Genetic results also indicate that Ccr4-Not acts downstream of the V-ATPase to promote TORC1 function. Whether this regulation is direct or indirect is not known currently. Question marks indicate important questions that remain to be addressed going forward.