Sorting secretory proteins

A receptor protein called TGN46 has an important role in sorting secretory proteins into vesicles going to different destinations inside cells

Getting mRNA-Containing Ribonucleoprotein Granules Out of a Nuclear Back Door

A pivotal feature of long-lasting synaptic plasticity is the localization of RNAs and the protein synthesis machinery at synaptic sites. How and where ribonucleoprotein (RNP) transport granules that support this synthetic activity are formed is of fundamental importance. The prevailing model poses that the nuclear pore complex (NPC) is the sole gatekeeper for transit of cellular material in and out of the nucleus. However, insights from the nuclear assembly of large viral capsids highlight a back door route for nuclear escape, a process referred to nuclear envelope (NE) budding. Recent studies indicate that NE budding might be an endogenous cellular process for the nuclear export of very large RNPs and protein aggregates. In Drosophila, this mechanism is required for synaptic plasticity, but its role may extend beyond the nervous system, in tissues where local changes in translation are required. Here we discuss these recent findings and a potential relationship between NE budding and the NPC

Oligomerization and endocytosis of Hedgehog is necessary for its efficient exovesicular secretion

Hedgehog (Hh) is a secreted morphogen, involved in both short and long range signaling necessary for tissue patterning during development. It is unclear how this dually lipidated protein is transported over a long range in the aqueous milieu of interstitial spaces. We had previously shown that the long range signaling of Hh requires its oligomerization. Here we show that Hh is secreted in the form of exovesicles. These are derived by the endocytic delivery of cell surface Hh to multi vesicular bodies (MVBs) via an endosomal sorting complex required for transport (ECSRT)-dependent process. Perturbations of ESCRT proteins have a selective effect on long-range Hh signaling in Drosophila wing imaginal discs. Importantly oligomerization-defective Hh is inefficiently incorporated into exovesicles due to its poor endocytic delivery to MVBs. These results provide evidence that nanoscale organization of Hh regulates the secretion of Hh on ESCRT-derived exovesicles, which in turn act as a vehicle for long range signaling

Liquid-liquid phase separation facilitates the biogenesis of secretory storage granules.

Funder: Yale-start up grantFunder: NIGMS NIH HHSFunder: Fraternal Order of Eagles Diabetes Research CenterFunder: Sir Henry DaleFunder: University of IowaFunder: PI Daniel EberlFunder: Royal Society210481Insulin is synthesized by pancreatic β-cells and stored into secretory granules (SGs). SGs fuse with the plasma membrane in response to a stimulus and deliver insulin to the bloodstream. The mechanism of how proinsulin and its processing enzymes are sorted and targeted from the trans-Golgi network (TGN) to SGs remains mysterious. No cargo receptor for proinsulin has been identified. Here, we show that chromogranin (CG) proteins undergo liquid-liquid phase separation (LLPS) at a mildly acidic pH in the lumen of the TGN, and recruit clients like proinsulin to the condensates. Client selectivity is sequence-independent but based on the concentration of the client molecules in the TGN. We propose that the TGN provides the milieu for converting CGs into a "cargo sponge" leading to partitioning of client molecules, thus facilitating receptor-independent client sorting. These findings provide a new receptor-independent sorting model in β-cells and many other cell types and therefore represent an innovation in the field of membrane trafficking