A transport protein in Aspergillus nidulans maintains the right concentration of nitrogen compounds within cells by actively responding to the presence of nutrient sources.

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Too much of a good thing is no good. Even microorganisms must know when to stop absorbing nutrients from their environment before they reach toxic concentrations. The fungus, Aspergillus nidulans, developed a clever strategy centered around a membrane-bound transport protein called UapA that functions to import nitrogen sources, including uric acid and xanthine, into the cell. Once the cell is satiated with enough uric acid and xanthine, UapA is sent to the cell's recycling machinery where it's broken down to its constituent building block amino acids for use elsewhere. Curiously, it is the presence of uric acid and xanthine that trigger UapA to transport them into the cell in the first place, and it is these same compounds that mark UapA for recycling once the cell's nitrogen requirements have been satisfied.

Uric acid and xanthine promote increased synthesis of UapA to facilitate their transport into the cell, but then induce break down of UapA once they are inside the cell. While the mechanisms are not yet fully understood, it appears that something inherent in the transportation of uric acid or xanthin across the cell membrane leads to subtle conformational changes in the shape of UapA, thereby signaling the cell to begin breaking it apart. It is attractive to hypothesize that the purpose of this unusual inhibitory pathway is to serve as a negative-feedback loop to prevent over accumulation of uric acid that may result in cellular damage. That may in fact be the case, but other pieces of evidence, including the low toxicity of uric acid to the fungus, shed doubt on the concept. As such, the precise reasons for this evolutionary adaptation remain unknown.

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"In the presence of substrates, UapA is endocytosed, sorted into the multivesicular body pathway and degraded in vacuoles. Substrate-induced endocytosis, unlike ammonium-induced turnover, is absolutely dependent on UapA activity and...the signal for increased endocytosis is the actual translocation of substrates through the UapA protein...transport-dependent UapA endocytosis occurs through a mechanism, which senses subtle conformational changes associated with the transport cycle...The principal signal for transporter regulated trafficking, endocytosis and entry into multivesicular bodies (MVBs), which eventually fuse with the vacuole/lysosome and thus deliver the vesicles to degradative enzymes, is their ubiquitination...Ubiquitination serves as a signal not only for internalization from the plasma membrane, but also to redirect newly synthesized transporter molecules from the Golgi to endosomes and for MVB sorting." (Gournas et al. 2010:246)

"Purines, through their oxidation to uric acid (UA), induce UapA transcription several fold, through the action of the pathway-specific transcriptional regulator UaY. However, UapA transcription is only possible in the absence of NH4...UA-elicited sorting of UapA into the multivesicular pathway and its degradation in vacuoles." (Gournas et al. 2010:247)

"The fact that 3mX, a high-affinity ligand of UapA, failed to provoke UapA endocytosis was somehow unexpected and led us to conclude that the signal for UapA turnover is substrate transport rather than substrate or ligand binding...substrates lead to increased UapA-GFP vacuolar degradation...all substrates resulting in UapA turnover are also inducers of UapA transcription...We found that concentrations of UA in the range of 5–20 mM did not induce UapA transcription, but were sufficient to elicit UapA turnover." (Gournas et al. 2010:248)

"[E]fficient binding and transport of substrates are prerequisites for endosomal sorting." (Gournas et al. 2010:250-1)

"Lys572 is a critical residue for both substrate- and ammonium-elicited UapA endocytosis, very probably by being the site of ubiquitin addition by HulA...UA-triggered internalization acts exclusively on plasma membrane-bound UapA. On the other hand, in the presence of NH4, UapA-GFP was mostly in vacuoles and endosome-like particles, suggesting that a significant fraction of UapA might be directly sorted into the MVB pathway." (Gournas et al. 2010:253)

"[D]e novo made UapA is not sensitive to enhanced turnover by substrates prior to its translocation in the plasma membrane...substrate-elicited sorting of plasma membrane UapA into the endosomal degradative pathway is absolutely dependent on transport activity and that conformational changes associated with the transport cycle underlie UapA endocytosis." (Gournas et al. 2010:254-5)

"UapA is the first example of a transporter regulated by its substrates by two antagonistic mechanisms; transcriptional induction and enhanced endocytosis...substrate-induced turnover of transporters is generally believed to have evolved as a negative feedback control for avoiding excess uptake of potentially toxic metabolites." (Gournas et al. 2010:256)

Journal article
Transport-dependent endocytosis and turnover of a uric acid-xanthine permeaseMolecular MicrobiologyDecember 11, 2009
Christos Gournas, Sotiris Amillis, Anna Vlanti, George Diallinas

Transport-dependent endocytosis and turnover of a uric acid-xanthine permease

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Living System/s

Aspergillus nidulansSpecies

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