A Conserved Role for SNX9-Family Members in the Regulation of Phagosome Maturation during Engulfment of Apoptotic Cells

Clearance of apoptotic cells is of key importance during development, tissue homeostasis and wound healing in multi-cellular animals. Genetic studies in the nematode Caenorhabditis elegans have identified a set of genes involved in the early steps of cell clearance, in particular the recognition and internalization of apoptotic cells. A pathway that orchestrates the maturation of phagosomes containing ingested apoptotic cells in the worm has recently been described. However, many steps in this pathway remain elusive. Here we show that the C. elegans SNX9-family member LST-4 (lateral signaling target) and its closest mammalian orthologue SNX33 play an evolutionary conserved role during apoptotic cell corpse clearance. In lst-4 deficient worms, internalized apoptotic cells accumulated within non-acidified, DYN-1-positive but RAB-5-negative phagosomes. Genetically, we show that LST-4 functions at the same step as DYN-1 during corpse removal, upstream of the GTPase RAB-5. We further show that mammalian SNX33 rescue C. elegans lst-4 mutants and that overexpression of truncated SNX33 fragments interfered with phagosome maturation in a mammalian cell system. Taken together, our genetic and cell biological analyses suggest that LST-4 is recruited through a combined activity of DYN-1 and VPS-34 to the early phagosome membrane, where it cooperates with DYN-1 to promote recruitment/retention of RAB-5 on the early phagosomal membrane during cell corpse clearance. The functional conservation between LST-4 and SNX33 indicate that these early steps of apoptotic phagosome maturation are likely conserved through evolution

A coupled calibration and modelling approach to the understanding of dry-land lake oxygen isotope records

Comparisons between climate proxies and instrumental records through the last two centuries are often used to understand better the controls on palaeoarchives and to find relationships that can be used to quantify changes in pre-instrumental climate. Here we compare an 80-year-long annually resolved oxygen isotope record from Nar Gölü, Turkey, a varved lake sequence, with instrumental records of temperature, precipitation, wind speed, relative humidity and calculated values of evaporation, all of which are known to be possible controls on lake oxygen isotope systems. Significant relationships are found between the isotope record and summer temperatures and evaporation suggesting these are dominant controls on the isotope hydrology of this non-outlet lake. Modelling the stable isotope hydrology of the lake system allows these relationships to be tested independently. We show that the isotope record follows the same trends in the temperature and evaporation records but that, even when combined, these two climatic factors cannot fully explain the magnitude of change observed in the isotope record. The models show the lake system is much less sensitive to changes in evaporation and temperature than the climate calibration suggests. Additional factors, including changes in the amount of precipitation, are required to amplify the isotope change. It is concluded that proxy-climate calibrations may incorrectly estimate the amplitude of past changes in individual climate parameters, unless validated independently