Cellular homeostasis is maintained by quality control (QC) pathways that counteract the potentially deleterious effects of intra – or extracellular stresses. Although much is known about the signaling pathways that control individual physiological responses to stress, yet our understanding of how signaling from different organelles / cellular compartments is integrated into a single cellular network that coordinates a multi-faceted response is still in its infancy. Our group, a “baby team” created in January 2018, aims at unraveling the intricate relationships between a novel yeast nuclear mRNA biogenesis/export QC pathway mediated by the chromatin remodeler Isw1 (Babour et al. 2016), and endoplasmic reticulum (ER) stress response pathways.
ISWI mediated QC
In eukaryotes, mRNA biogenesis in the nucleus and their translation in the cytoplasm are physically separated by the nuclear envelope. The accurate formation of export-competent messenger ribonucleoparticles (mRNPs) results from the precise spatio-temporal orchestration of highly coordinated synthesis and processing reactions, followed by their transport via the nuclear pore complex to the cytoplasm where they are in turn translated into proteins. Nuclear retention is one of the cell’s quality control (QC) strategies to handle suboptimal mRNPs: we recently demonstrated that nuclear retention of premature mRNPs was initiated at the chromatin level via the chromatin remodeling complex ISWI, which is able to directly interact with RNA. Intriguingly, the interaction between Isw1 and mRNAs is also observed in wild-type conditions. We want to elucidate whether these interactions can influence gene expression by affecting the nuclear vs cytoplasmic localization of mRNPs.
Figure 1: ISWI-mediated nuclear mRNP retention. Right: defective mRNP are retained in the nucleus via a direct interaction with Isw1, preventing their export in the cytoplasm. Left: In wild-type cells, the Isw1-mRNA interaction is transient and does not prevent nuclear export.
Endoplasmic Reticulum stress QC
The ER is the largest membrane-bound cell organelle with many vital functions, including protein folding and lipid synthesis. When the ER folding capacity is outcompeted by the load of newly synthesized polypeptides, misfolded proteins accumulate and cause ER stress. ER stress activates an adaptive transcriptional pathway, the unfolded protein response (UPR), which increases the protein folding capacity of the ER and induces ER-associated degradation (ERAD). Interestingly, ISW1 is a UPR target gene, suggesting it may participate to the regulation of ER homeostasis. In addition, ER stress triggers the ER surveillance pathway (ERSU), a non-transcriptional pathway, which monitors the ER status to ensure the transmission of a functional organelle to the progeny (Bicknell A. et al, 2007; Babour. A et al., 2010). The ERSU is independent of the UPR and operates through the MAP kinase Slt2. While Slt2 is activated under a variety of stimuli, a comprehensive picture of its downstream targets is lacking. It is thus conceivable that a number of yet unidentified downstream targets of Slt2 participate in distinct outputs the ER stress response.
Using a combination of biochemical, genetic, genome-wide and microscopy approaches, we aim to identify the molecular cross-talks between these QC pathways and to understand their functional significance in the maintenance of ER homeostasis. ER stress is a hallmark of many pathological conditions including cardiac malfunction, metabolic disorders, neurodegeneration or cancer. While we are currently exploring these processes in budding yeast, we intend to expand our work to mammalian cells in the future.
► Dargemont C, Babour A (2017) Novel functions for chromatin dynamics in mRNA biogenesis beyond transcription. Nucleus. 8:482-488.
► Babour A*, Shen Q, Dos-Santos J, Murray S, Gay A, Challal D, Fasken M, Palancade B, Corbett A, Libri D, Mellor J, Dargemont C. (2016) The Chromatin Remodeler ISW1 Is a Quality Control Factor that Surveys Nuclear mRNP Biogenesis. Cell. 167:1201-1214. (*= corresponding author, lead author)
► Niño CA, Hérissant L, Babour A, Dargemont C (2013) mRNA export in yeast. Chem Rev. 113: 8523-45.
► Vitaliano-Prunier A*, Babour A*, Hérissant L*, Apponi L, Margaritis T, Holstege FC, Corbett AH, Gwizdek C, Dargemont C (2012) H2B ubiquitylation controls the formation of export-competent mRNP. Mol Cell. 45:132-139. (*= shared first co-authors).
► Babour A, Bicknell AA, Tourtellotte J, Niwa M. (2010) A surveillance pathway monitors the fitness of the endoplasmic reticulum to control its inheritance. Cell. 142: 256-69.
► Bicknell A, Babour A, Federovitch CM, Niwa M (2007) A novel role in cytokinesis reveals a housekeeping function for the unfolded protein response. J Cell Biol. 177: 1017-27.