Maintenance of cellular lipidostasis by the COP9 signalosome, a fundamental regulator of proteostasis

The COP9 signalosome (CSN) is an enzymatic multi-subunit protein complex conserved in all eukaryotes, which typically consists of 8 subunits. The CSN is a key regulator of cellular proteostasis playing a role in various functions, including the response to DNA damage, lifespan, and development. Null mutants of each of the subunits in plants and animals result in embryonic lethality. The catalytic subunit of CSN, Csn5, is overproduced in many human cancers, and its overproduction often correlates with poor survival. However, in various fungal species from unicellular yeast to filamentous fungi, the number of CSN subunits is smaller, and knockdown of subunits is viable with mild defective phenotypes in circadian clock, cell cycle, pheromone response, and fruit body formation. Therefore, these organisms are suitable models for studying unique and common cellular CSN functions.

We performed transcriptomic analysis, genome-wide proteomic screening, and phenotypic assessments of Δcsn5, a null mutant Csn5 in S. cerevisiae, and observed downregulation of 90 genes involved in fatty acid and lipid biosynthesis. We also confirmed that Csn5 is necessary for efficient ergosterol biosynthesis. Furthermore, we measured reduced ergosterol levels in Δcsn5, a Ko mutant of the CSN catalytic subunit in S. cerevisiae, S. pombe, C. albicans, and A. nidulans. Molecular characterization of Δcsn5 of S. cerevisiae demonstrated instability of Mga2/Spt23 (an ER membrane sensor that serves as a transcription activator of ergosterol biosynthesis), correlated with altered lipid homeostasis. We also found that disorder in lipid homeostasis further aggravates ER dysfunction and impairs plasma membrane composition and formation. Considering that Spt23/Mga2 pathway is not conserved in few of the abovementioned species, our results support the view that Csn5 maintains the membranes composition that is required for sensing by unrelated (i.e. nonorthologous) but functionally analogous activators of ergosterol biosynthesis.