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Starvation poses a fundamental challenge to cell survival. Whereas the role of autophagy in promoting energy homeostasis in this setting has been extensively characterized.sup.1, other mechanisms are less well understood. Here we reveal that glyceraldehyde 3-phosphate dehydrogenase (GAPDH) inhibits coat protein I (COPI) transport by targeting a GTPase-activating protein (GAP) towards ADP-ribosylation factor 1 (ARF1) to suppress COPI vesicle fission. GAPDH inhibits multiple other transport pathways, also by targeting ARF GAPs. Further characterization suggests that this broad inhibition is activated by the cell during starvation to reduce energy consumption. These findings reveal a remarkable level of coordination among the intracellular transport pathways that underlies a critical mechanism of cellular energy homeostasis.During starvation, glyceraldehyde 3-phosphate dehydrogenase (GAPDH) targets GTPase-activating proteins to inhibit multiple intracellular transport pathways, thereby promoting energy homeostasis., Author(s): Jia-Shu Yang [sup.1] , Jia-Wei Hsu [sup.1] , Seung-Yeol Park [sup.1] , Jian Li [sup.1] , William M. Oldham [sup.2] , Galina V. Beznoussenko [sup.3] , Alexander A. Mironov [...]

The coat protein I (COPI) complex mediates retrograde trafficking from the Golgi to the endoplasmic reticulum (ER). Five siblings with persistent bacterial and viral infections and defective humoral and cellular immunity had a homozygous p.K652E mutation in the [gamma]1 subunit of COPI ([gamma]1-COP). The mutation disrupts COPI binding to the KDEL receptor and impairs the retrieval of KDEL-bearing chaperones from the Golgi to the ER. Homozygous Copg[1.sup.K652E] mice had increased ER stress in activated T and B cells, poor antibody responses, and normal numbers of T cells that proliferated normally, but underwent increased apoptosis upon activation. Exposure of the mutants to pet store mice caused weight loss, lymphopenia, and defective T cell proliferation that recapitulated the findings in the patients. The ER stress- relieving agent tauroursodeoxycholic acid corrected the immune defects of the mutants and reversed the phenotype they acquired following exposure to pet store mice. This study establishes the role of [gamma]1-COP in the ER retrieval of KDEL-bearing chaperones and thereby the importance of ER homeostasis in adaptive immunity., Introduction During infection, microbial antigens and pathogen-associated molecular pattern molecules activate B and T lymphocytes to proliferate and secrete antibodies and cytokines that help eliminate the invading organisms. Secretory proteins, [...]

The COPI complex, which has a role in retrograde transport through the Golgi, is shown to also mediate anterograde tubular transport through the Golgi; in response to external stimuli, the small GTPase CDC42 acts as an essential modulator of bidirectional Golgi transport, and promotes the sorting of cargoes destined for anterograde transport into the tubules at the expense of those targeted for retrograde transport. Two-way traffic through Golgi complex tubules The Golgi complex consists of a series of plate-like stacks, connected by structures called tubules. It has been called the cell's 'post office', given its central role in the sorting and distribution of proteins to their proper intracellular destination. Here Victor Hsu and colleagues provide evidence that Golgi tubules play a role in anterograde transport from Golgi towards plasma membrane -- a process previously thought to be mediated primarily by the Golgi stacks. They find that the COPI protein complex, known to play a part in retrograde transport through the Golgi, also mediates anterograde tubular transport. This raises the question of how COPI can sort cargoes for transport in opposite directions. The authors find that in response to external stimuli, the small GTPase CDC42 is an essential modulator of bidirectional Golgi transport, promoting the sorting of cargoes destined for anterograde transport into the tubules at the expense of those targeted for retrograde transport. The Golgi complex has a central role in the intracellular sorting of secretory proteins.sup.1,2. Anterograde transport through the Golgi has been explained by the movement of Golgi cisternae, known as cisternal maturation.sup.3,4,5. Because this explanation is now appreciated to be incomplete.sup.6, interest has developed in understanding tubules that connect the Golgi cisternae.sup.7,8,9. Here we show that the coat protein I (COPI) complex sorts anterograde cargoes into these tubules in human cells. Moreover, the small GTPase CDC42 regulates bidirectional Golgi transport by targeting the dual functions of COPI in cargo sorting and carrier formation. CDC42 also directly imparts membrane curvature to promote COPI tubule formation. Our findings further reveal that COPI tubular transport complements cisternal maturation in explaining how anterograde Golgi transport is achieved, and that bidirectional COPI transport is modulated by environmental cues through CDC42., Author(s): Seung-Yeol Park [sup.1] [sup.2] , Jia-Shu Yang [sup.1] [sup.2] , Angela B. Schmider [sup.2] [sup.3] , Roy J. Soberman [sup.2] [sup.3] [sup.4] , Victor W. Hsu [sup.1] [sup.2] Author [...]

Signaling through the Ror2 receptor tyrosine kinase promotes invadopodia formation for tumor invasion. Here, we identify intraflagellar transport 20 (IFT20) as a new target of this signaling in tumors that lack primary cilia, and find that IFT20 mediates the ability of Ror2 signaling to induce the invasiveness of these tumors. We also find that IFT20 regulates the nucleation of Golgi-derived microtubules by affecting the GM130-AKAP450 complex, which promotes Golgi ribbon formation in achieving polarized secretion for cell migration and invasion. Furthermore, IFT20 promotes the efficiency of transport through the Golgi complex. These findings shed new insights into how Ror2 signaling promotes tumor invasiveness, and also advance the understanding of how Golgi structure and transport can be regulated.

Studies on vesicle formation by the Coat Protein I (COPI) complex have contributed to a basic understanding of how vesicular transport is initiated. Phosphatidic acid (PA) and diacylglycerol (DAG) have been found previously to be required for the fission stage of COPI vesicle formation. Here, we find that PA with varying lipid geometry can all promote early fission, but only PA with shortened acyl chains promotes late fission. Moreover, diacylglycerol (DAG) acts after PA in late fission, with this role of DAG also requiring shorter acyl chains. Further highlighting the importance of the short-chain lipid geometry for late fission, we find that shorter forms of PA and DAG promote the vesiculation ability of COPI fission factors. These findings advance a general understanding of how lipid geometry contributes to membrane deformation for vesicle fission, and also how proteins and lipids coordinate their actions in driving this process. Phosphatidic acid and diacylglycerol are required for COPI vesicle fission. Here, the authors find that shorter forms of these lipids promote the late stage of COPI vesicle fission, further suggesting how lipid geometry contributes to membrane deformation in driving fission. [ABSTRACT FROM AUTHOR]

Intracellular transport among organellar compartments occurs in two general ways, by membrane-bound carriers or membrane contacts. Specific circumstances that involve the coordination of these two modes of transport remain to be defined. Studying Coat Protein I (COPI) transport, we find that phosphatidylcholine with short acyl chains (sPC) is delivered through membrane contact from the endoplasmic reticulum (ER) to sites of COPI vesicle formation at the Golgi to support the fission stage. Phosphatidylinositol transfer protein beta (PITPβ) plays a key role in this process, with the elucidation of this role advancing a new understanding of how PITPβ acts, providing a mechanistic understanding of a specific circumstance when vesicular transport requires membrane contact, and contributing to a basic understanding of how transport carriers in a model intracellular pathway are formed., Competing Interests: Disclosure and competing interest statement The authors declare no competing interests.