Endoplasmic reticulum (ER) to Golgi trafficking is an essential step in sorting mature, correctly folded, processed and assembled proteins (cargo) from immature proteins and ER-resident proteins. However, the mechanisms governing trafficking selectivity, specificity and regulation are not yet fully understood. To date, three complementary mechanisms have been described that enable regulation of this trafficking step: ER retention of immature proteins in the ER; selective uptake of fully mature proteins into Golgi-bound vesicles; and retrieval from the Golgi of immature cargo that has erroneously exited the ER. Together, these three mechanisms allow incredible specificity and enable the cell to carry out protein quality control and regulate protein processing, oligomerization and expression. This review will focus on the current knowledge of selectivity mechanisms acting during the ER-to-Golgi sorting step and their significance in health and disease. The review will also highlight several key questions that have remained unanswered and discuss the future frontiers.

Plant architecture is a predictable but flexible trait. The timing and position of organ initiation from the shoot apical meristem (SAM) contribute to the final plant form. While much progress has been made recently in understanding how the site of leaf initiation is determined, the mechanism underlying the temporal interval between leaf primordia is still largely unknown. The Arabidopsis ZRIZI (ZRZ) gene belongs to a large gene family encoding multidrug and toxic compound extrusion (MATE) transporters. Unique among plant MATE transporters identified so far, ZRZ is localized to the membrane of a small organelle, possibly the mitochondria. Plants overexpressing ZRZ in initiating leaves are short, produce leaves much faster than wild-type plants and show enhanced growth of axillary buds. These results suggest that ZRZ is involved in communicating a leaf-borne signal that determines the rate of organ initiation.

The endoplasmic reticulum (ER) is the entry site of proteins into the endomembrane system.Proteins exit the ER via coat protein II (COPII) vesicles in a selective manner, mediated either by direct interaction with the COPII coat or aided by cargo receptors. Despite the fundamental role of such receptors in protein sorting, only a few have been identified. To further define the machinery that packages secretory cargo and targets proteins from the ER to Golgi membranes, we used multiple systematic approaches, which revealed 2 uncharacterized proteins that mediate the trafficking and maturation of Pma1, the essential yeast plasma membrane proton ATPase. Ydl121c (Exp1) is an ER protein that binds Pma1, is packaged into COPII vesicles, and whose deletion causes ER retention of Pma1. Ykl077w (Psg1) physically interacts with Exp1 and can be found in the Golgi and coat protein I (COPI) vesicles but does not directly bind Pma1. Loss of Psg1 causes enhanced degradation of Pma1 in the vacuole. Our findings suggest that Exp1 is a Pma1 cargo receptor and that Psg1 aids Pma1 maturation in the Golgi or affects its retrieval. More generally our work shows the utility of high content screens in the identification of novel trafficking components.The endoplasmic reticulum (ER) is the entry site for proteins into the endomembrane system. Once appropriately folded, non-ER resident proteins are routed to the Golgi apparatus for further maturation and distribution.1 Proteins exit the ER via coat protein II (COPII) vesicles.Although some proteins are captured by stochastic sampling of the ER lumen and membrane in a process called bulk flow, 2,3 more efficient and regulated sorting relies on selective uptake into vesicles.Additional sorting specificity occurs by retrieval of ER residents or immature proteins from the Golgi apparatus to the ER through coat protein I (COPI) vesicles. 4,5 The general mechanisms of vesicle formation are well characterized, yet the molecular basis that governs specific recognition between the coats, and the diverse range of proteins that must be packaged into vesicles, is yet to be fully described. To perturb traffic we chose to use mutations in the cargo binding sites of Sec24 as it was already shown that a mutation in the Sec24-A binding site perturbs ER-Golgi vesicular traffic. 26 Moreover, the 2 -best-characterized cargo of the A-and C-sites are SNARE proteins that act in anterograde (Sed5) and retrograde (Sec22) traffic, suggesting that bidirectional traffic between the ER and Golgi would be perturbed in these mutants. In contrast, many cargo that engage the Bsite are proteins that move forward in the secretory pathway. Thus we focused on A-and C-site mutations that should more specifically perturb ER-Golgi vesicular traffic. 6,7 We used automated mating techniques to integrate these Sec24 binding site mutants into the secretome-GFP library 27 and imaged the resulting strains using a high content setup ( Figure 1A).

Weed control is essential in modern agriculture, though it has become more difficult with the emergence of resistance to most current herbicides and a slow registration process of new compounds. A new approach to identify possible herbicide candidates using an artificial intelligence algorithm that takes into effect biological parameters with the goal of reducing R&D time on new herbicides. Herein we describe the discovery of 4-chloro-2-pentenamides as novel inhibitors of protoporphyrinogen oxidase, a known herbicide target site, by the Agrematch AI. The herbicidal activity is confirmed in greenhouse assays, with the highest performing AGR001 showing good activity pre-emergent at 150 g/ha and post emergent as low as 50 g/ha on the troublesome weed palmer amaranth (Amaranthus palmeri). A lack of activity is reported on PPO resistant palmer amaranth carrying the glycine 210 deletion (ΔG210) mutation. The mechanism of action is confirmed by the herbicide-dependent accumulation of protoporphyrin IX, subsequent light-dependent loss of membrane integrity, and direct in vitro inhibition of protoporphyrinogen oxidase. Modeling of the docking of these inhibitors in the active site of protoporphyrinogen oxidase illustrates that their flexible side chains can accommodate a number of poses in the catalytic domain.