Mechanistic Insights into Manganese Induced Down - Regulation of the Cis Golgi Glycoprotein GPP130

<p>During invasion of host cells the Shigella bacterial toxin sorts away from degradative lysosomes and traffics to the Golgi complex by binding the cycling transmembrane protein GPP130 as GPP130 returns from endosomes to the Golgi. Remarkably, an increase in Golgi manganese (Mn) alters the trafficking of GPP130 causing its degradation in lysosomes thereby protecting cells against lethal doses of purified toxin. Mn-induced down-regulation of GPP130 is thus an important paradigm for therapy against the incurable Shiga toxicosis as well as metal-regulated protein sorting in the Golgi. The experiments herein reveal significant aspects of the mechanism. We identified a transferable trafficking determinant within the GPP130 lumenal stem domain that bound Mn and observed that Mn binding induced its oligomerization in the Golgi. Significantly, alanine substitutions that blocked Mn binding abrogated both oligomerization and GPP130 sorting to lysosomes. GPP130 oligomers engaged the canonical Golgi-lysosomal trafficking machinery, as GPP130 exit from the Golgi required the sorting adaptor GGA1 and the clathrin vesicle coat complex. Surprisingly, oligomerization was sufficient since GPP130 redistributed to lysosomes in the absence of Mn by forced aggregation using a drug-controlled selfinteracting version of the FKBP domain. Further, neither the cytoplasmic domain nor residues in the lumenal stem domain critical for normal GPP130 cycling were required for this redistribution. These observations suggested that higher order oligomerization might generally cause lysosomal targeting of Golgi membrane proteins. Indeed, induced oligomerization of two other unrelated Golgi proteins caused their redistribution to endosome/lysosome-like punctae and subsequent degradation. The ER-based unfolded protein response was not activated during this process. Altogether, these results show that Mn binds and oligomerizes GPP130 targeting it to what may be a pre-existing quality control pathway in the Golgi where aggregated proteins are degraded in lysosomes.</p

Manganese induces oligomerization to promote down-regulation of the intracellular trafficking receptor used by Shiga toxin.

<p>Manganese (Mn) protects cells against lethal doses of purified Shiga toxin by causing the degradation of the cycling transmembrane protein GPP130, which the toxin uses as a trafficking receptor. Mn-induced GPP130 down-regulation, in addition to being a potential therapeutic approach against Shiga toxicosis, is a model for the study of metal regulated protein sorting. Significantly, however, the mechanism by which Mn regulates GPP130 trafficking is unknown. Here we show that a transferable trafficking determinant within GPP130 bound Mn and that Mn binding induced GPP130 oligomerization in the Golgi. Alanine substitutions blocking Mn binding abrogated both oligomerization of GPP130 and GPP130 sorting from the Golgi to lysosomes. Further, oligomerization was sufficient because forced aggregation, using a drug-controlled polymerization domain, redirected GPP130 to lysosomes in the absence of Mn. These experiments reveal metal-induced oligomerization as a Golgi sorting mechanism for a clinically relevant receptor for Shiga toxin.</p

Indian Economy : Selected Methodological Advances

This paper develops tools to examine selected major issues in the Indian economy. The study computes the potential growth rate of the economy and the agricultural sector, extends the analysis of the fiscal stimulus and its effects, and estimates the short and long run elasticities of India’s trade. This brings out the need for structural reforms in raising the potential growth rate of economy and that of agriculture to achieve a non-inflationary, high growth trajectory for the country. The fiscal stimulus effects indicate the importance of fiscal consolidation efforts to sustain high growth. The trade elasticities buttress the case for maintaining an appropriate real effective exchange rate.India, agriculture, Stimulus, exports, Imports, trade

The Paris Agreement: resolving the inconsistency between global goals and national contributions

The adoption of the Paris Agreement in December 2015 moved the world a step closer to avoiding dangerous climate change. The aggregated individual intended nationally determined contributions (INDCs) are not yet sufficient to be consistent with the long-term goals of the agreement of ‘holding the increase in global average temperature to well below 2°C’ and ‘pursuing efforts’ towards 1.5°C. However, the Paris Agreement gives hope that this inconsistency can be resolved. We find that many of the contributions are conservative and in some cases may be overachieved. We also find that the preparation of the INDCs has advanced national climate policy-making, notably in developing countries. Moreover, provisions in the Paris Agreement require countries to regularly review, update and strengthen these actions. In addition, the significant number of non-state actions launched in recent years is not yet adequately captured in the INDCs. Finally, we discuss decarbonization, which has happened faster in some sectors than expected, giving hope that such a transition can also be accomplished in other sectors. Taken together, there is reason to be optimistic that eventually national action to reduce emissions will be more consistent with the agreed global temperature limits

Assessment of the potentials to increase emissions reduction targets by the major GHGs emitters taking into consideration technological and political feasibility: In the framework of the project: "Implikationen des Pariser Klimaschutzabkommens auf nationale Klimaschutzanstrengungen"

This report shows the potential distribution of the emissions reduction efforts between different Parties based on different approaches and presents an in-depth assessment of the circumstances influencing the (over-) achievement of the currently suggested emissions reduction goals. The analysis focuses on the following countries: Brazil, Canada, China, Germany, India, Japan and the United States