Abstract
Eukaryotic cells respond to stress and changes in the environment in part by repressing translation and forming cytoplasmic assemblies called stress granules and P-bodies, which harbor non-translating mRNAs and proteins. A third, but poorly understood, assembly called the eIF2B body can form and contains the eIF2B complex, an essential guanine exchange factor for the translation initiation factor eIF2. Hypomorphic EIF2B alleles can lead to Vanishing White Matter Disease (VWMD), a leukodystrophy that causes progressive white matter loss. An unexplored question is how eIF2B body formation is controlled and whether VWMD alleles in EIF2B alter the formation of eIF2B bodies, stress granules, or P-bodies. To examine these issues, we assessed eIF2B body, stress granule, and P-body induction in wild-type yeast cells and cells carrying VWMD alleles in the EIF2B2 (GCD7) and EIF2B5 (GCD6) subunits of eIF2B. We demonstrate eIF2B bodies are rapidly and reversibly formed independently of stress granules during acute glucose deprivation. VWMD mutations had diverse effects on stress-induced assemblies with some alleles altering eIF2B bodies, and others leading to increased P-body formation. Moreover, some VWMD-causing mutations in GCD7 caused hyper-sensitivity to chronic GCN2 activation, consistent with VWMD mutations causing hyper-sensitivity to eIF2α phosphorylation and thereby impacting VWMD pathogenesis.
Highlights
Translation factors play important roles in shaping the organization of the cytosol
We describe cellular conditions that affect eIF2B body formation, which will be important for understanding the formation and function of eIF2B bodies
In contrast to previous reports that eIF2B bodies are abundantly formed in normal conditions[5,8], our results indicate that eIF2B bodies occur in less than 10% of cells under normal conditions at log phase, but are rapidly induced by glucose deprivation stress and during stationary phase when glucose is limiting
Summary
Translation factors play important roles in shaping the organization of the cytosol. During stress, translation suppression induces the formation and/or expansion of macromolecular complexes enriched in non-translating mRNAs, translation factors and RNA binding proteins including processing bodies (P-bodies) and stress granules (SGs)[1,2,3,4]. Understanding the full set and dynamics of stress-induced complexes will be important for understanding how cells adapt to and survive stress conditions Another class of cytoplasmic assemblies in yeast that contain translation factors, referred to as eIF2B bodies, are less well understood. An interesting connection between eIF2B and neurodegenerative disease is that the leukodystrophy Vanishing White Matter Disease (VWMD) is caused by mutations in the genes encoding any of the five subunits of the eIF2B complex[13]. We hypothesized that eIF2B bodies, like SGs and P-bodies, are dynamic, inducible assemblies that form during conditions of acute stress when the cytoplasm is acidic and translation is repressed. We investigated whether mutations in EIF2B2 genes that cause VWMD perturb the formation of eIF2B bodies, SGs or P-bodies by affecting the structure or function of the eIF2B complex (respectively)
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