ZFPL1, a novel ring finger protein required for cis-Golgi integrity and efficient ER-to-Golgi transport.

The Golgi apparatus occupies a central position within the secretory pathway, but the molecular mechanisms responsible for its assembly and organization remain poorly understood. We report here the identification of zinc finger protein-like 1 (ZFPL1) as a novel structural component of the Golgi apparatus. ZFPL1 is a conserved and widely expressed integral membrane protein with two predicted zinc fingers at the N-terminus, the second of which is a likely ring domain. ZFPL1 directly interacts with the cis-Golgi matrix protein GM130. Depletion of ZFPL1 results in the accumulation of cis-Golgi matrix proteins in the intermediate compartment (IC) and the tubulation of cis-Golgi and IC membranes. Loss of ZFPL1 function also impairs cis-Golgi assembly following brefeldin A washout and slows the rate of cargo trafficking into the Golgi apparatus. Effects upon Golgi matrix protein localization and cis-Golgi structure can be rescued by wild-type ZFPL1 but not mutants defective in GM130 binding. Together, these data suggest that ZFPL1 has an important function in maintaining the integrity of the cis-Golgi and that it does so through interactions with GM130.

An unintended experiment in fisheries science: a marine area protected by war results in Mexican waves in fish numbers-at-age.

Marine protected areas (MPAs) are attaining increasing importance in the management of marine ecosystems. They are effective for conservation in tropical and subtropical areas (mainly coral and rocky reefs), but it is debated whether they are useful in the management of migratory fish stocks in open temperate regions. World War II created a large marine area within which commercial fishing was prevented for 6 years. Here we analyse scientific trawl data for three important North Sea gadoids, collected between 1928 and 1958. Using statistical models to summarise the data, we demonstrate the potential of MPAs for expediting the recovery of over-exploited fisheries in open temperate regions. Our age-structured data and population models suggest that wild fish stocks will respond rapidly and positively to reductions in harvesting rates and that the numbers of older fish in a population will react before, and in much greater proportion, than their younger counterparts in a kind of Mexican wave. Our analyses demonstrate both the overall increase in survival due to the lack of harvesting in the War and the form of the age-dependent wave in numbers. We conclude that large closed areas can be very useful in the conservation of migratory species from temperate areas and that older fish benefit fastest and in greater proportion. Importantly, any rise in spawning stock biomass may also not immediately result in better recruitment, which can respond more slowly and hence take longer to contribute to higher future harvestable biomass levels.

Maturity dispersion, stock auto-correlation, and management strategy in exploited populations.

Fishery management policies need to be based on historical summaries of stock status which are well correlated with the size of the group of individuals who will be affected by any harvest. This paper is motivated by the problem of managing stocks of Atlantic salmon, which can be accurately monitored during the riverine stages of their life-history, but which spend a lengthy period at sea before returning to spawn. We begin by formulating a minimal stochastic model of stock-recruitment driven population dynamics, which linearises to a standard ARMA form. We investigate the relation between maturity dispersion and the auto-covariance of stock fluctuations driven by process noise in the recruitment process and/or random variability in survival from recruitment to spawning. We demonstrate that significant reductions in fluctuation intensity and/or increases in long-run average yield can be achieved by controlling harvesting in response to the value of a historical summary focussed on lags at which the uncontrolled population dynamics produce strong correlations. We apply our minimal model to two well-characterised Atlantic salmon populations, and find poor agreement between predicted and observed stock fluctuation ACF. Re-examination of the ancilliary data available for one of our two exemplary systems leads us to propose an extended model which also linearises to ARMA form, and which predicts a fluctuation ACF more closely in agreement with that observed, and could thus form a satisfactory vehicle for policy discussion.

Discovery and Optimization of Allosteric Inhibitors of Mutant Isocitrate Dehydrogenase 1 (R132H IDH1) Displaying Activity in Human Acute Myeloid Leukemia Cells.

A collaborative high throughput screen of 1.35 million compounds against mutant (R132H) isocitrate dehydrogenase IDH1 led to the identification of a novel series of inhibitors. Elucidation of the bound ligand crystal structure showed that the inhibitors exhibited a novel binding mode in a previously identified allosteric site of IDH1 (R132H). This information guided the optimization of the series yielding submicromolar enzyme inhibitors with promising cellular activity. Encouragingly, one compound from this series was found to induce myeloid differentiation in primary human IDH1 R132H AML cells in vitro.

Targeting of the type II inositol polyphosphate 5-phosphatase INPP5B to the early secretory pathway.

The inositol polyphosphate 5-phosphatase INPP5B is closely related to the Lowe syndrome protein OCRL1, sharing a similar substrate specificity, domain organisation and an ability to compensate for loss of OCRL1 in knockout mice. The cellular localisation and functions of INPP5B have remained poorly defined until recently, when a role within the endocytic pathway was suggested. Here, we report that INPP5B is also localised to the early secretory pathway including the Golgi apparatus and ER-to-Golgi intermediate compartment (ERGIC). Consistent with this localisation, INPP5B binds to specific RAB proteins within the secretory pathway, and mutational analysis indicates that RAB binding is required for efficient Golgi targeting of INPP5B. Unlike OCRL1, INPP5B interacts with neither clathrin nor alpha-adaptin and is largely absent from clathrin-coated intermediates. Expression of INPP5B but not OCRL1 alters the distribution of the cycling protein ERGIC53 when cells are incubated at low temperature (15 degrees C) or in the presence of brefeldin A, causing ERGIC53 to accumulate in the ERGIC, with a concomitant loss from the ER. Our data suggest a role for INPP5B in retrograde ERGIC-to-ER transport and imply that it has functions distinct from those of OCRL1 within both the secretory and endocytic pathways.

Membrane targeting and activation of the Lowe syndrome protein OCRL1 by rab GTPases.

The X-linked disorder oculocerebrorenal syndrome of Lowe is caused by mutation of the OCRL1 protein, an inositol polyphosphate 5-phosphatase. OCRL1 is localised to the Golgi apparatus and early endosomes, and can translocate to lamellipodia upon growth factor stimulation. We show here that OCRL1 interacts with several members of the rab family of small GTPases. Strongest interaction is seen with Golgi-associated rab1 and rab6 and endosomal rab5. Point mutants defective in rab binding fail to target to the Golgi apparatus and endosomes, strongly suggesting rab interaction is required for targeting of OCRL1 to these compartments. Membrane recruitment via rab binding is required for changes in Golgi and endosomal dynamics induced by overexpression of catalytically inactive OCRL1. In vitro experiments demonstrate that rab5 and rab6 directly stimulate the 5-phosphatase activity of OCRL1. We conclude that rabs play a dual role in regulation of OCRL1, firstly targeting it to the Golgi apparatus and endosomes, and secondly, directly stimulating the 5-phosphatase activity of OCRL1 after membrane recruitment.