A THEMIS:SHP1 complex promotes T‐cell survival

THEMIS is critical for conventional T‐cell development, but its precise molecular function remains elusive. Here, we show that THEMIS constitutively associates with the phosphatases SHP1 and SHP2. This complex requires the adapter GRB2, which bridges SHP to THEMIS in a Tyr‐phosphorylation‐independent fashion. Rather, SHP1 and THEMIS engage with the N‐SH3 and C‐SH3 domains of GRB2, respectively, a configuration that allows GRB2‐SH2 to recruit the complex onto LAT. Consistent with THEMIS‐mediated recruitment of SHP to the TCR signalosome, THEMIS knock‐down increased TCR‐induced CD3‐ζ phosphorylation, Erk activation and CD69 expression, but not LCK phosphorylation. This generalized TCR signalling increase led to augmented apoptosis, a phenotype mirrored by SHP1 knock‐down. Remarkably, a KI mutation of LCK Ser59, previously suggested to be key in ERK‐mediated resistance towards SHP1 negative feedback, did not affect TCR signalling nor ligand discrimination in vivo. Thus, the THEMIS:SHP complex dampens early TCR signalling by a previously unknown molecular mechanism that favours T‐cell survival. We discuss possible implications of this mechanism in modulating TCR output signals towards conventional T‐cell development and differentiation.     

Introduction and spread of Thiara granifera (Lamarck, 1822) in Martinique, French West Indies

We followed the invasion dynamics of the Oriental thiarid snail Thiara granifera on the Martinique island, French Antilles. This freshwater species was first discovered in 1991 in the Charpentier River, and its spread has since been analysed based on a yearly survey of the malacological fauna at more than 100 sites covering the whole island and representing 50 river systems and three pools. Four river systems were sampled at many sites. Thirteen river systems were colonized by 1997. Colonization within river systems occurred at a speed greater than 1km per year, probably resulting from both active and passive dispersal. Our results can, on the whole, be explained by a simple diffusion process. However, stratified diffusion has to be invoked in at least one river. Moreover, colonization was faster downstream than upstream, suggesting that current velocity plays a significant role in dispersal. Dispersal also occurred between river systems at a mean distance of almost 10km, though with a large variance, in accordance with the scattered colony model of stratified diffusion. The relative frequencies of T. granifera and Melanoides tuberculata, another recent invader of Martinique, were followed at three sites on the Lézarde River. The first species quickly outnumbered the second, though never wiped it out. The data therefore do not support any exclusion phenomena between these two parthenogenetic invaders. Our analysis does not indicate any obvious influence of the rise of T. granifera on the local freshwater fauna.     

Phosphorylation, lipid raft interaction and traffic of alpha-synuclein in a yeast model for Parkinson

Parkinson's disease is a neurodegenerative disorder characterized by the formation of Lewy bodies containing aggregated alpha-synuclein. We used a yeast model to screen for deletion mutants with mislocalization and enhanced inclusion formation of alpha-synuclein. Many of the mutants were affected in functions related to vesicular traffic but especially mutants in endocytosis and vacuolar degradation combined inclusion formation with enhanced alpha-synuclein-mediated toxicity. The screening also allowed for identification of casein kinases responsible for alpha-synuclein phosphorylation at the plasma membrane as well as transacetylases that modulate the alpha-synuclein membrane interaction. In addition, alpha-synuclein was found to associate with lipid rafts, a phenomenon dependent on the ergosterol content. Together, our data suggest that toxicity of alpha-synuclein in yeast is at least in part associated with endocytosis of the protein, vesicular recycling back to the plasma membrane and vacuolar fusion defects, each contributing to the obstruction of different vesicular trafficking routes.