Plasma Membrane MCC/Eisosome Domains Promote Stress Resistance in Fungi

Abstract

There is growing appreciation that the plasma membrane orchestrates a diverse array of functions by segregating different activities into specialized domains that vary in size, stability, and composition. Studies with the budding yeast Saccharomyces cerevisiae have identified a novel type of plasma membrane domain known as the MCC (membrane compartment of Can1)/eisosomes that correspond to stable furrows in the plasma membrane. MCC/eisosomes maintain proteins at the cell surface, such as nutrient transporters like the Can1 arginine symporter, by protecting them from endocytosis and degradation. Recent studies from several fungal species are now revealing new functional roles for MCC/eisosomes that enable cells to respond to a wide range of stressors, including changes in membrane tension, nutrition, cell wall integrity, oxidation, and copper toxicity. The different MCC/eisosome functions are often intertwined through the roles of these domains in lipid homeostasis, which is important for proper plasma membrane architecture and cell signaling. Therefore, this review will emphasize the emerging models that explain how MCC/eisosomes act as hubs to coordinate cellular responses to stress. The importance of MCC/eisosomes is underscored by their roles in virulence for fungal pathogens of plants, animals, and humans, which also highlights the potential of these domains to act as novel therapeutic targets.

Keywords: Lsp1; MCC; Pil1; Slm1; Sur7; eisosome; furrow; membrane curvature; stress; yeast.

FIG 1

Landmark research that converged to develop the current models for MCC/eisosome structure. PM furrows were discovered by freeze-etch EM (14). Sur7-GFP (9) and Can1-GFP (7, 8) were found to localize to stable PM patches termed MCC domains. Pil1-GFP was subsequently found to associate with the cytoplasmic side of the MCC in a complex termed the eisosome (10). Immuno-EM studies then revealed that MCC/eisosomes correspond to PM furrows with Sur7 found at the tops, whereas Pil1 was detected at the bottom (13). Determining the structure of Lsp1 revealed it to be a BAR domain protein (16), and demonstration of the ability of Pil1 and Lsp1 to bind membranes and form filaments that shape the furrows led to the “half-pipe” model for MCC/eisosome structure (18). New high-resolution microscopy methods are revealing dynamic aspects of MCC/eisosome furrow structure in response to stress (21, 22, 49). Space limitations prevent showing other key advances, which are described in the text. (The image of the PM furrows is reproduced from reference with permission of Rockefeller University Press, the images of GFP-tagged Sur7 are reproduced from reference with permission, the image of GFP-tagged Can1 is reproduced from reference with permission, and the image of GFP-tagged Pil1 is reproduced from reference with permission of Springer Nature.)

FIG 2

Diversity of PM domains in S. cerevisiae. Illustration of different types of PM domains. MCC/eisosomes are stable under steady-state conditions and do not move laterally in the PM. Other domains are transient, such as sites of endocytosis, secretion, and cER tethering, or they diffuse laterally in the PM. Sensor domains include the ambient pH sensor (pH), the membrane compartment of TORC2 (MCT), cell wall integrity sensors (CWI), and Mss4 (phosphatidylinositol 4-phosphate 5-kinase). Note that the MCP (membrane compartment of Pma1) domain is not specifically labeled in the figure, as it is thought to comprise all the areas of the PM that are not occupied by the domains mentioned above. Recent studies also indicate that additional domains can be identified by high-resolution fluorescence microscopy (2, 20, 44).

FIG 3

Proteins associated with MCC/eisosomes. A subset of proteins that localize to MCC/eisosomes shown in Table 1 is illustrated. Proteins that can exit the furrows under stress are also shown outside the furrows on the right (i.e., Nce102, Slm1/2, and APC family symporters such as Can1). Sur7 and Can1 localize to the tops of the furrows (13, 35, 49). Pil1, Lsp1, Seg1, and Pkh1/2 appear to localize to the bottom of the furrows (18, 22, 37, 61). The other proteins were positioned where space was available and do not reflect experimentally determined locations.

FIG 4

MCC/eisosome functions. MCC/eisosome functions are displayed according to the different sections in which they are described in the text.

FIG 5

Regulation of APC family nutrient symporters. Model of APC symporter regulation in MCC/eisosomes, which rely on a proton gradient across the PM to transport substrate into the cell. The symporters cluster to the upper region of the MCC/eisosome (in light blue) in an outward-facing (OF) conformation. The presence of substrate induces a transition to an inward-facing (IF) conformation, which enables the symporter to exit the MCC and exposes a site in the N-terminal tail that binds an arrestin-related trafficking adaptor (ART). The arrestin then recruits the Rps5 ubiquitin ligase that transfers ubiquitin onto lysine residues in the N-terminal tail of symporter, leading to endocytosis and degradation in the vacuole. This model was adapted from several studies, including the following: references , , , , , and .

FIG 6

PM Furrow shape varies across fungal species. (A) S. cerevisiae furrows are short and punctate and show random orientation. Scale bar represents 100 nm, the arrow indicates diagonal striations, and the asterisk indicates structure that is thought to correspond to a cluster of Pma1 proteins (170). (B) Short, punctate furrows from unidentified species of bread mold. Scale bar represents 100 nm; the arrow points to cell wall remnants. (C) Long furrows in S. pombe. Scale bar represents 100 nm. The arrow points to diagonal striations, and an asterisk indicates an anastomosing furrow with reduced depth. (D) Long, anastomosing furrows in C. neoformans. Scale bar represents 50 nm. (E) Highly dense, wavy furrows in lichenized Candelaria concolor. Scale bar represents 500 nm. (All images are reproduced from reference with permission.)