α-Arrestins, also called arrestin-related trafficking adaptors (ARTs), constitute a large family of proteins conserved from yeast to humans. Despite their evolutionary precedence over their extensively studied relatives of the β-arrestin family, α-arrestins have been discovered relatively recently, and thus their properties are mostly unexplored. The predominant function of α-arrestins is the selective identification of membrane proteins for ubiquitination and degradation, which is an important element in maintaining membrane protein homeostasis as well as global cellular metabolisms. Among members of the arrestin clan, only α-arrestins possess PY motifs that allow canonical binding to WW domains of Rsp5/NEDD4 ubiquitin ligases and the subsequent ubiquitination of membrane proteins leading to their vacuolar/lysosomal degradation. The molecular mechanisms of the selective substrate’s targeting, function, and regulation of α-arrestins in response to different stimuli remain incompletely understood. Several functions of α-arrestins in animal models have been recently characterized, including redox homeostasis regulation, innate immune response regulation, and tumor suppression. However, the molecular mechanisms of α-arrestin regulation and substrate interactions are mainly based on observations from the yeast Saccharomyces cerevisiae model. Nonetheless, α-arrestins have been implicated in health disorders such as diabetes, cardiovascular diseases, neurodegenerative disorders, and tumor progression, placing them in the group of potential therapeutic targets.

In the face of flourishing industrialization and global trade, heavy metal and metalloid contamination of the environment is a growing concern throughout the world. The widespread presence of highly toxic compounds of arsenic, antimony, and cadmium in nature poses a particular threat to human health. Prolonged exposure to these toxins has been associated with severe human diseases, including cancer, diabetes, and neurodegenerative disorders. These toxins are known to induce analogous cellular stresses, such as DNA damage, disturbance of redox homeostasis, and proteotoxicity. To overcome these threats and improve or devise treatment methods, it is crucial to understand the mechanisms of cellular detoxification in metal and metalloid stress. Membrane proteins are key cellular components involved in the uptake, vacuolar/lysosomal sequestration, and efflux of these compounds; thus, deciphering the multilevel regulation of these proteins is of the utmost importance. In this review, we summarize data on the mechanisms of arsenic, antimony, and cadmium detoxification in the context of membrane proteome. We used yeast Saccharomyces cerevisiae as a eukaryotic model to elucidate the complex mechanisms of the production, regulation, and degradation of selected membrane transporters under metal(loid)-induced stress conditions. Additionally, we present data on orthologues membrane proteins involved in metal(loid)-associated diseases in humans.

Plasma membrane integrity maintenance is crucial for cell survival. Plasma membrane proteins are under tight regulation and under certain conditions are actively removed from the membrane allowing cells to adapt to changing environment. Proteins blocked in the cell membrane may interact with other molecules and form toxic aggregates. Ubiquitin is one of the most important modifiers targeting proteins for degradation and/or regulating protein functions. Several quality control mechanisms have been identified in eukaryotic cells: chaperone- dependent system that recognizes and ubiquitinates misfolded or redundant membrane proteins; protein-intrinsic LID-degron system, based on recognition of degron and ARTs-Rsp5 network that controls quality of membrane transporters. Rsp5, a Nedd4-family E3 ubiquitin ligase, is crucial for plasma membrane proteins ubiquitination. Rsp5-dependent ubiquitin action acts as a sorting signal for internalization of a membrane protein via endocytosis, recognition by the ESCRT system and vacuolar degradation. Rsp5 builds poliUb-chains on K63 and recognizes substrates through various adaptor proteins. Most of the identified Rsp5 adaptors belongs to the α-arrestin family. Plasma membrane protein ubiquitination and degradation disorders may cause neurodegenerative and cardiovascular diseases. The yeast Saccharomyces cerevisiae is one of the best models for studying trafficking pathways of membrane proteins and ubiquitination systems.