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Autophagy Publication details, including instructions for authors and subscription information: http://www.tandfonline.com/loi/kaup20
The intersection of Golgi-ER retrograde and autophagic trafficking a
a
a
a
Shanshan He , Douglas O’Connell , Xiaowei Zhang , Yongfei Yang & Chengyu Liang
a
a
Department of Molecular Microbiology and Immunology; University of Southern California; Los Angeles, CA USA Published online: 15 Nov 2013.
Click for updates To cite this article: Shanshan He, Douglas O’Connell, Xiaowei Zhang, Yongfei Yang & Chengyu Liang (2014) The intersection of Golgi-ER retrograde and autophagic trafficking, Autophagy, 10:1, 180-181, DOI: 10.4161/auto.26917 To link to this article: http://dx.doi.org/10.4161/auto.26917
PLEASE SCROLL DOWN FOR ARTICLE Taylor & Francis makes every effort to ensure the accuracy of all the information (the “Content”) contained in the publications on our platform. However, Taylor & Francis, our agents, and our licensors make no representations or warranties whatsoever as to the accuracy, completeness, or suitability for any purpose of the Content. Any opinions and views expressed in this publication are the opinions and views of the authors, and are not the views of or endorsed by Taylor & Francis. The accuracy of the Content should not be relied upon and should be independently verified with primary sources of information. Taylor and Francis shall not be liable for any losses, actions, claims, proceedings, demands, costs, expenses, damages, and other liabilities whatsoever or howsoever caused arising directly or indirectly in connection with, in relation to or arising out of the use of the Content. This article may be used for research, teaching, and private study purposes. Any substantial or systematic reproduction, redistribution, reselling, loan, sub-licensing, systematic supply, or distribution in any form to anyone is expressly forbidden. Terms & Conditions of access and use can be found at http:// www.tandfonline.com/page/terms-and-conditions
Autophagic Punctum
Autophagy 10:1, 180–181; January 2014; © 2014 Landes Bioscience
The intersection of Golgi-ER retrograde and autophagic trafficking Shanshan He, Douglas O’Connell, Xiaowei Zhang, Yongfei Yang, and Chengyu Liang*
F
Keywords: UVRAG, Golgi-ER trafficking, autophagy Submitted: 10/16/2013 Accepted: 10/22/2013 http://dx.doi.org/10.4161/auto.26787 *Correspondence to: Chengyu Liang; Email: [email protected] Punctum to: He S, Ni D, Ma B, Lee JH, Zhang T, Ghozalli I, Pirooz SD, Zhao Z, Bharatham N, Li B, et al. PtdIns(3)P-bound UVRAG coordinates Golgi-ER retrograde and Atg9 transport by differential interactions with the ER tether and the beclin 1 complex. Nat Cell Biol 2013; 15:1206–19; PMID:24056303; http://dx.doi.org/10.1038/ ncb2848
or decades, a marvelous amount of work has been performed to identify molecules that regulate distinct stages of membrane transport in the ER-Golgi secretory pathway and autophagy, which are implicated in many human diseases. However, an important missing piece in this puzzle is how the cell dynamically coordinates these crisscrossed trafficking pathways in response to different stimuli. Our recent study has identified UVRAG as a mode-switching protein that coordinates Golgi-ER retrograde and autophagic trafficking. UVRAG recognizes phosphatidylinositol-3phosphate (PtdIns3P) and locates to the ER, where it couples the ER tethering complex containing RINT1 to govern Golgi-ER retrograde transport. Intriguingly, when autophagy is induced, UVRAG undergoes a “partnering shift” from the ER tethering complex to the BECN1 autophagy complex, resulting in concomitant inhibition of Golgi-ER transport and the activation of ATG9 autophagic trafficking. Therefore, Golgi-ER retrograde and autophagyrelated membrane trafficking are functionally interdependent and tightly regulated by UVRAG to ensure spatiotemporal fidelity of protein transport and organelle homeostasis, providing distinguished insights into trafficking-related diseases. The ER and Golgi are at the heart of the secretory pathway that is responsible for protein synthesis, modification, and sorting. Disruption of ER and Golgi homeostasis affects a wide network of proteins and pathways that will in turn
180 Autophagy
lead to disease. Trafficking between the ER and Golgi is bidirectional. Especially, Golgi-ER retrograde transport is not only necessary for membrane recycling to maintain organelle homeostasis, but also serves as a quality-control mechanism to return wayward proteins that have escaped from their ER residence. Hence, the Golgi-ER retrograde pathway must be finely tuned to ensure the fidelity of protein transport between the ER and Golgi and the maintenance of steady-state distribution of proteins. Regulation of Golgi-ER trafficking is mediated by specific phosphoinositides, which serve as signals or binding platforms for effector proteins to direct membrane flow. PtdIns3P was previously thought to be mainly located in the endosome as an essential regulator of endocytic, phagocytic, and autophagic trafficking. However, an abundant basal level of PtdIns3P was recently found in the ER where little was known about its function. Our recent work identified UVRAG, an autophagy-related protein, as a PtdIns3Pbinding protein through its C2 domain, which locates it to the ER. The ER-related phosphatase MTMR3 or the PI/PtdIns 3-kinase inhibitor wortmannin dissociates UVRAG from the ER membrane, indicating that UVRAG is a downstream effector of PtdIns3P. Furthermore, PtdIns3P-anchored UVRAG acts as a scaffold to recruit the RINT1-containing tether onto PtdIns3P-rich domains of the ER. UVRAG directly interacts with RINT1, and this interaction enhances the efficiency of COPI-coated cargo delivery. Depletion of UVRAG or blocking its interaction with PtdIns3P compromises
Volume 10 Issue 1
©2014 Landes Bioscience. Do not distribute.
Downloaded by [University of Western Ontario] at 03:43 06 February 2015
Department of Molecular Microbiology and Immunology; University of Southern California; Los Angeles, CA USA
Downloaded by [University of Western Ontario] at 03:43 06 February 2015
the function of UVRAG in Golgi-to-ER retrograde traffic and disrupts cis-Golgi structure. To the best of our knowledge, this is the first time that the physiological role of PtdIns3P and UVRAG is established in Golgi-ER trafficking. UVRAG couples PtdIns3P metabolism and COPI carriers to ensure the correct direction of transport and dynamic equilibrium between the Golgi and ER. In addition to their role in Golgi-ER trafficking under physiological conditions, we found that the interaction between UVRAG and PtdIns3P is essential in ATG9 trafficking during autophagy. UVRAGK78A,R82A, a UVRAG mutant that losses the ability to interact with PtdIns3P, disrupts redistribution of Golgi-derived ATG9 that is involved in autophagosome formation. Since the Golgi and ER are regarded as the main membrane sources for the biogenesis of autophagosomes, when UVRAG loses its interaction with PtdIns3P, the resulting defective ATG9 autophagic trafficking observed may be just a consequence of compromised Golgi-ER trafficking. However, when RINT1 is knocked down, we observe an apparent disruption of Golgi structure and Golgi-ER transport, but no discernible effect on Golgi-related ATG9 trafficking. These results suggest that the cellular pathways that mediate retrograde transport and autophagyrelated membrane trafficking are differentially regulated. PtdIns3P-bound UVRAG, which is at the intersection
of Golgi-ER retrograde trafficking and autophagic trafficking, has a direct role in regulating both pathways independently. Indeed, we found that UVRAG serves both trafficking pathways by assembling different protein complexes under different conditions. Under normal physiological conditions, most UVRAG interacts with the RINT1 complex, and couples PtdIns3P signals to ensure the optimal kinetics of Golgi-derived COPI transport. Nutrient deficiency or rapamycin treatment dissociates UVRAG from the RINT1 complex, resulting in the inhibition of Golgi-ER retrograde transport. Meanwhile, UVRAG recruits the BECN1-SH3GLB1/Bif-1-PIK3C3PIK3R4 autophagy complex, to allow the redistribution of ATG9 membranous compartments, likely helping the correct tethering and fusion of Atg9containing vesicles with the PtdIns3Pand LC3-positive phagophores. The dual functionality of PtdIns3P-bound UVRAG suggests that Golgi-ER transport and ATG9-mediated autophagic trafficking are intimately coordinated. Moreover, this interconnection may promote cellular selfadaption: under nutrient-rich conditions, autophagy decontaminates the cell at low levels, while the early secretory pathway is well maintained to ensure diverse cellular functions; conversely, when cells are under starvation or stress, they are engaged in autophagy to decrease energy consumption for survival while the early secretory pathway is compromised.
This study clearly establishes the dual role of PtdIns3P-bound UVRAG in both Golgi-ER retrograde transport and autophagy, which also poses interesting questions. First, is there any other phosphoinositide involved in Golgi-ER trafficking? In fact, UVRAG binds to PtdIns4P in vitro and partially overlaps with the PtdIns4P-enriched trans-Golgi network, but its molecular function remains unclear. Furthermore, what carries out the “partnering shift” on UVRAG in response to different stimuli? One possibility is that UVRAG function is posttranslationally regulated and different stimuli trigger differential modifications on UVRAG, resulting in selective affinities to different partners. Regardless of these uncertainties, we identified UVRAG as a mode-switching trafficking effector, which couples PtdIns3P metabolism to coordinate Golgi-ER retrograde transport and ATG9-mediated autophagic trafficking by targeting 2 separate complexes, containing RINT1 and BECN1. Given the role of the early secretory pathway and autophagy in maintaining organelle homeostasis and cell survival, this newly defined cellular self-adaptation mechanism provides an exceptional therapeutic opportunity in traffickingrelated diseases. Disclosure of Potential Conflicts of Interest
No potential conflicts of interest were disclosed.
www.landesbioscience.com Autophagy 181
©2014 Landes Bioscience. Do not distribute.
Autophagic Punctum
Autophagic Punctum
Autophagy Publication details, including instructions for authors and subscription information: http://www.tandfonline.com/loi/kaup20
The intersection of Golgi-ER retrograde and autophagic trafficking a
a
a
a
Shanshan He , Douglas O’Connell , Xiaowei Zhang , Yongfei Yang & Chengyu Liang
a
a
Department of Molecular Microbiology and Immunology; University of Southern California; Los Angeles, CA USA Published online: 15 Nov 2013.
Click for updates To cite this article: Shanshan He, Douglas O’Connell, Xiaowei Zhang, Yongfei Yang & Chengyu Liang (2014) The intersection of Golgi-ER retrograde and autophagic trafficking, Autophagy, 10:1, 180-181, DOI: 10.4161/auto.26917 To link to this article: http://dx.doi.org/10.4161/auto.26917
PLEASE SCROLL DOWN FOR ARTICLE Taylor & Francis makes every effort to ensure the accuracy of all the information (the “Content”) contained in the publications on our platform. However, Taylor & Francis, our agents, and our licensors make no representations or warranties whatsoever as to the accuracy, completeness, or suitability for any purpose of the Content. Any opinions and views expressed in this publication are the opinions and views of the authors, and are not the views of or endorsed by Taylor & Francis. The accuracy of the Content should not be relied upon and should be independently verified with primary sources of information. Taylor and Francis shall not be liable for any losses, actions, claims, proceedings, demands, costs, expenses, damages, and other liabilities whatsoever or howsoever caused arising directly or indirectly in connection with, in relation to or arising out of the use of the Content. This article may be used for research, teaching, and private study purposes. Any substantial or systematic reproduction, redistribution, reselling, loan, sub-licensing, systematic supply, or distribution in any form to anyone is expressly forbidden. Terms & Conditions of access and use can be found at http:// www.tandfonline.com/page/terms-and-conditions
Autophagic Punctum
Autophagy 10:1, 180–181; January 2014; © 2014 Landes Bioscience
The intersection of Golgi-ER retrograde and autophagic trafficking Shanshan He, Douglas O’Connell, Xiaowei Zhang, Yongfei Yang, and Chengyu Liang*
F
Keywords: UVRAG, Golgi-ER trafficking, autophagy Submitted: 10/16/2013 Accepted: 10/22/2013 http://dx.doi.org/10.4161/auto.26787 *Correspondence to: Chengyu Liang; Email: [email protected] Punctum to: He S, Ni D, Ma B, Lee JH, Zhang T, Ghozalli I, Pirooz SD, Zhao Z, Bharatham N, Li B, et al. PtdIns(3)P-bound UVRAG coordinates Golgi-ER retrograde and Atg9 transport by differential interactions with the ER tether and the beclin 1 complex. Nat Cell Biol 2013; 15:1206–19; PMID:24056303; http://dx.doi.org/10.1038/ ncb2848
or decades, a marvelous amount of work has been performed to identify molecules that regulate distinct stages of membrane transport in the ER-Golgi secretory pathway and autophagy, which are implicated in many human diseases. However, an important missing piece in this puzzle is how the cell dynamically coordinates these crisscrossed trafficking pathways in response to different stimuli. Our recent study has identified UVRAG as a mode-switching protein that coordinates Golgi-ER retrograde and autophagic trafficking. UVRAG recognizes phosphatidylinositol-3phosphate (PtdIns3P) and locates to the ER, where it couples the ER tethering complex containing RINT1 to govern Golgi-ER retrograde transport. Intriguingly, when autophagy is induced, UVRAG undergoes a “partnering shift” from the ER tethering complex to the BECN1 autophagy complex, resulting in concomitant inhibition of Golgi-ER transport and the activation of ATG9 autophagic trafficking. Therefore, Golgi-ER retrograde and autophagyrelated membrane trafficking are functionally interdependent and tightly regulated by UVRAG to ensure spatiotemporal fidelity of protein transport and organelle homeostasis, providing distinguished insights into trafficking-related diseases. The ER and Golgi are at the heart of the secretory pathway that is responsible for protein synthesis, modification, and sorting. Disruption of ER and Golgi homeostasis affects a wide network of proteins and pathways that will in turn
180 Autophagy
lead to disease. Trafficking between the ER and Golgi is bidirectional. Especially, Golgi-ER retrograde transport is not only necessary for membrane recycling to maintain organelle homeostasis, but also serves as a quality-control mechanism to return wayward proteins that have escaped from their ER residence. Hence, the Golgi-ER retrograde pathway must be finely tuned to ensure the fidelity of protein transport between the ER and Golgi and the maintenance of steady-state distribution of proteins. Regulation of Golgi-ER trafficking is mediated by specific phosphoinositides, which serve as signals or binding platforms for effector proteins to direct membrane flow. PtdIns3P was previously thought to be mainly located in the endosome as an essential regulator of endocytic, phagocytic, and autophagic trafficking. However, an abundant basal level of PtdIns3P was recently found in the ER where little was known about its function. Our recent work identified UVRAG, an autophagy-related protein, as a PtdIns3Pbinding protein through its C2 domain, which locates it to the ER. The ER-related phosphatase MTMR3 or the PI/PtdIns 3-kinase inhibitor wortmannin dissociates UVRAG from the ER membrane, indicating that UVRAG is a downstream effector of PtdIns3P. Furthermore, PtdIns3P-anchored UVRAG acts as a scaffold to recruit the RINT1-containing tether onto PtdIns3P-rich domains of the ER. UVRAG directly interacts with RINT1, and this interaction enhances the efficiency of COPI-coated cargo delivery. Depletion of UVRAG or blocking its interaction with PtdIns3P compromises
Volume 10 Issue 1
©2014 Landes Bioscience. Do not distribute.
Downloaded by [University of Western Ontario] at 03:43 06 February 2015
Department of Molecular Microbiology and Immunology; University of Southern California; Los Angeles, CA USA
Downloaded by [University of Western Ontario] at 03:43 06 February 2015
the function of UVRAG in Golgi-to-ER retrograde traffic and disrupts cis-Golgi structure. To the best of our knowledge, this is the first time that the physiological role of PtdIns3P and UVRAG is established in Golgi-ER trafficking. UVRAG couples PtdIns3P metabolism and COPI carriers to ensure the correct direction of transport and dynamic equilibrium between the Golgi and ER. In addition to their role in Golgi-ER trafficking under physiological conditions, we found that the interaction between UVRAG and PtdIns3P is essential in ATG9 trafficking during autophagy. UVRAGK78A,R82A, a UVRAG mutant that losses the ability to interact with PtdIns3P, disrupts redistribution of Golgi-derived ATG9 that is involved in autophagosome formation. Since the Golgi and ER are regarded as the main membrane sources for the biogenesis of autophagosomes, when UVRAG loses its interaction with PtdIns3P, the resulting defective ATG9 autophagic trafficking observed may be just a consequence of compromised Golgi-ER trafficking. However, when RINT1 is knocked down, we observe an apparent disruption of Golgi structure and Golgi-ER transport, but no discernible effect on Golgi-related ATG9 trafficking. These results suggest that the cellular pathways that mediate retrograde transport and autophagyrelated membrane trafficking are differentially regulated. PtdIns3P-bound UVRAG, which is at the intersection
of Golgi-ER retrograde trafficking and autophagic trafficking, has a direct role in regulating both pathways independently. Indeed, we found that UVRAG serves both trafficking pathways by assembling different protein complexes under different conditions. Under normal physiological conditions, most UVRAG interacts with the RINT1 complex, and couples PtdIns3P signals to ensure the optimal kinetics of Golgi-derived COPI transport. Nutrient deficiency or rapamycin treatment dissociates UVRAG from the RINT1 complex, resulting in the inhibition of Golgi-ER retrograde transport. Meanwhile, UVRAG recruits the BECN1-SH3GLB1/Bif-1-PIK3C3PIK3R4 autophagy complex, to allow the redistribution of ATG9 membranous compartments, likely helping the correct tethering and fusion of Atg9containing vesicles with the PtdIns3Pand LC3-positive phagophores. The dual functionality of PtdIns3P-bound UVRAG suggests that Golgi-ER transport and ATG9-mediated autophagic trafficking are intimately coordinated. Moreover, this interconnection may promote cellular selfadaption: under nutrient-rich conditions, autophagy decontaminates the cell at low levels, while the early secretory pathway is well maintained to ensure diverse cellular functions; conversely, when cells are under starvation or stress, they are engaged in autophagy to decrease energy consumption for survival while the early secretory pathway is compromised.
This study clearly establishes the dual role of PtdIns3P-bound UVRAG in both Golgi-ER retrograde transport and autophagy, which also poses interesting questions. First, is there any other phosphoinositide involved in Golgi-ER trafficking? In fact, UVRAG binds to PtdIns4P in vitro and partially overlaps with the PtdIns4P-enriched trans-Golgi network, but its molecular function remains unclear. Furthermore, what carries out the “partnering shift” on UVRAG in response to different stimuli? One possibility is that UVRAG function is posttranslationally regulated and different stimuli trigger differential modifications on UVRAG, resulting in selective affinities to different partners. Regardless of these uncertainties, we identified UVRAG as a mode-switching trafficking effector, which couples PtdIns3P metabolism to coordinate Golgi-ER retrograde transport and ATG9-mediated autophagic trafficking by targeting 2 separate complexes, containing RINT1 and BECN1. Given the role of the early secretory pathway and autophagy in maintaining organelle homeostasis and cell survival, this newly defined cellular self-adaptation mechanism provides an exceptional therapeutic opportunity in traffickingrelated diseases. Disclosure of Potential Conflicts of Interest
No potential conflicts of interest were disclosed.
www.landesbioscience.com Autophagy 181
©2014 Landes Bioscience. Do not distribute.
Autophagic Punctum
Autophagic Punctum
