Life and Death of Fungal Transporters under the Challenge of Polarity

Abstract

Eukaryotic plasma membrane (PM) transporters face critical challenges that are not widely present in prokaryotes. The two most important issues are proper subcellular traffic and targeting to the PM, and regulated endocytosis in response to physiological, developmental, or stress signals. Sorting of transporters from their site of synthesis, the endoplasmic reticulum (ER), to the PM has been long thought, but not formally shown, to occur via the conventional Golgi-dependent vesicular secretory pathway. Endocytosis of specific eukaryotic transporters has been studied more systematically and shown to involve ubiquitination, internalization, and sorting to early endosomes, followed by turnover in the multivesicular bodies (MVB)/lysosomes/vacuole system. In specific cases, internalized transporters have been shown to recycle back to the PM. However, the mechanisms of transporter forward trafficking and turnover have been overturned recently through systematic work in the model fungus Aspergillus nidulans. In this review, we present evidence that shows that transporter traffic to the PM takes place through Golgi bypass and transporter endocytosis operates via a mechanism that is distinct from that of recycling membrane cargoes essential for fungal growth. We discuss these findings in relation to adaptation to challenges imposed by cell polarity in fungi as well as in other eukaryotes and provide a rationale of why transporters and possibly other housekeeping membrane proteins ‘avoid’ routes of polar trafficking.

Profile of Membrane Cargo Trafficking Proteins and Transporters Expressed under N Source Derepressing Conditions in Aspergillus nidulans

“…The final step of cargo vesicle fusion in the PM is assisted by components of the so-called exocyst complex, transfer to actin filaments and the tethering action of t-SNAREs. However, our recent work had challenged this generally accepted, but formally unproven, view concerning sorting of de novo made transporters to the PM [8,13]. Using the ascomycete Aspergillus nidulans, an emerging model system for studying membrane trafficking, we provided evidence that several nutrient transporters traffic non-polarly to the PM via Golgi-and microtubule-bypass.…”

“…Furthermore, eukaryotes seem to employ several points of protein quality control safeguarding that transporters are properly folded during the first steps of their initial biogenesis or remain structurally 'undamaged' under specific stress conditions. In case transporters are misfolded or damaged by chemical or physical stress or as a result of prolonged activity, cells employ processes such as endoplasmic reticulum-associated degradation (ERAD) and proteasome degradation, as well as specific chaperone-assisted selective autophagy [5] in addition to endocytosis, for driving transporter turnover [6][7][8][9]. A critical aspect of transporter function, associated to their transmembrane nature, is their continuous and dynamic interactions with membrane lipids, a challenge not faced by soluble proteins [10].…”

“…In brief, we have found that purine transporters distributed non-polarly along the entire length of the PM and polar cargoes involved in apical growth (e.g., chitin synthase, lipid flippases, etc.) use distinct mechanisms to be endocytosed [8]. In response to modification of the nutritional profile of the growth medium or due to prolonged activity, transporters are recognized by α-arrestin adaptors, which recruit a HECT-type ubiquitin ligase.…”

Internalization of the host alkaline pH signal in a fungal pathogen

“…This divergence could be explained by the unique way in which filamentous fungi traffic various proteins. Filamentous fungal membrane transporters can localize in a polar manner, whereas yeast membrane transporters generally localize homogenously in microdomains throughout the plasma membrane [54]. This has been linked to a different path the protein takes following synthesis in the ER.…”

“…This has been linked to a different path the protein takes following synthesis in the ER. Many of A. nidulans transporters bypass the Golgi apparatus and traffic directly to the plasma membrane following synthesis [54]. The ability for proteins to circumvent certain cellular components to a final destination could explain the endocytosis-independent mechanism of Pal pathway activation.…”