Regulation of the Sar1 GTPase Cycle Is Necessary for Large Cargo Secretion from the Endoplasmic Reticulum

Saito, Kota; Maeda, Miharu; Katada, Toshiaki

doi:10.3389/fcell.2017.00075

Cited by 51 publications

(48 citation statements)

References 98 publications

(133 reference statements)

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“…Notably, the divergent amino acids on the α-helix all appear on the exposed surface of the protein, suggesting that they may have a role in protein-protein interactions. Notably, the importance of the interaction between SEC31 and the SAR1 GTPase cycle for large cargo secretion has been well documented (6,(19)(20)(21). We hypothesized that the GTP-adjacent cluster of divergent residues may play a role in either GTP exchange or hydrolysis, whereas the SEC23/31-adjacent divergent helix may play a role in binding SEC31.…”

Section: Sar1a and Sar1b Have Two Clusters Of Divergent Amino Acidsmentioning

confidence: 98%

“…SAR1 then recruits the remainder of the COPII complex, SEC23/24 and SEC13/31 heterodimers, to the ER membrane (1)(2)(3)(4)(5). It is thought that regulation of the GTPase activity of SAR1 is important for large cargo selection (6). Thus, SAR1 has two important roles: Recruitment of the other COPII proteins, and controlling the timing of COPII budding with its GTPase cycle.…”

Section: Introductionmentioning

confidence: 99%

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SAR1 paralogs differ biochemically in assembly of the COPII coat

Studer

Schekman

2020

Preprint

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COPII-coated vesicles are the primary mediators of vesicular traffic from the ER to the Golgi apparatus. SAR1 is a small GTPase, which, upon GTP binding, recruits the other COPII proteins to the ER membrane. In mammals, there are two SAR1 paralogs which genetic data suggest may have distinct physiological roles, e.g. in lipoprotein secretion for SAR1B. We identified two clusters of amino acids that have conserved, paralog-specific sequences. One cluster is adjacent to the SAR1 GTP-binding pocket and alters the kinetics of GTP exchange. The other cluster is adjacent to the binding site of COPII components SEC31 and SEC23. We found that the latter cluster confers a SEC23A binding preference to SAR1B over SAR1A. In contrast to SAR1B, SAR1A is prone to oligomerize on a membrane surface. Importantly, in relation to its physiological function, SAR1B, but not SAR1A, can compensate for loss of SAR1B in lipoprotein secretion. The SEC31/SEC23-binding siteadjacent divergent cluster is critical for this function. These data identify the novel paralogspecific function for SAR1B, and provide insights into the mechanisms of large cargo secretion and COPII related diseases.

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Section: Sar1a and Sar1b Have Two Clusters Of Divergent Amino Acidsmentioning

confidence: 98%

Section: Introductionmentioning

confidence: 99%

SAR1 paralogs differ biochemically in assembly of the COPII coat

Studer

Schekman

2020

Preprint

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“…Using RNAi, we knocked down the expression of Sec16A and TANGO1, proteins which are required for efficient COPII transport [43]. We additionally knocked down cTAGE5 and Sec12; Sec12 is the guanine exchange factor for Sar1 GTPase, which in turn regulates COPII vesicle formation [48]. Sec12 also interacts with cTAGE5 at ERES, and it has been shown that cTAGE5 can recruit Sec12 to COPII budding sites [49].…”

Section: Depletion Of Eres Regulatory Proteins Disrupts Chlamydia Growthmentioning

confidence: 99%

Proximity-dependent proteomics of theChlamydia trachomatisinclusion membrane reveals functional interactions with endoplasmic reticulum exit sites

Dickinson

Anderson

Webb‐Robertson

et al. 2018

Preprint

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Chlamydia trachomatis is the most common bacterial sexually transmitted infection, responsible for millions of infections each year. Despite this high prevalence, the elucidation of the molecular mechanisms of Chlamydia pathogenesis has been difficult due to limitations in genetic tools and its intracellular developmental cycle. Within a host epithelial cell, chlamydiae replicate within a vacuole called the inclusion. Many Chlamydia-host interactions are thought to be mediated by the Inc family of type III secreted proteins that are anchored in the inclusion membrane, but their array of host targets are largely unknown. To investigate how the inclusion membrane proteome changes over the course of an infected cell, we have adapted the APEX system of proximity-dependent biotinylation. APEX is capable of specifically labeling proteins within a 20 nm radius in living cells. We transformed C. trachomatis to express the enzyme APEX fused to known inclusion membrane proteins, allowing biotinylation and pull-down of inclusion-associated proteins. Using quantitative mass spectrometry against APEX labeled samples, we identified over 400 proteins associated with the inclusion membrane at early, middle, and late stages of epithelial cell infection. This system was sensitive enough to detect inclusion interacting proteins early in the developmental cycle, at 8 hours post infection, a previously intractable time point. Mass spectrometry analysis revealed a novel, early association between C. trachomatis inclusions and endoplasmic reticulum exit sites (ERES), functional regions of the ER where COPII-coated vesicles originate. Pharmacological and genetic disruption of ERES function severely restricted early chlamydial growth and the development of infectious progeny. APEX is therefore a powerful in situ approach for identifying critical protein interactions on the membranes of pathogen-containing vacuoles. Furthermore, the data derived from proteomic mapping of Chlamydia inclusions has illuminated an important functional role for ERES in promoting chlamydial developmental growth.

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“…ARL8B is well characterized and has been shown to localize to lysosomes and regulate several aspects of lysosome biology, such as positioning and motility (Khatter et al, 2015). Finally, SARs play a well-described role in the budding of COPII-coated vesicles from the ER, while TRIM23 was implicated in antiviral defense and adipocyte differentiation (Arimoto et al, 2010;Watanabe et al, 2015;Saito et al, 2017).…”

Section: Introductionmentioning

confidence: 99%

The Role of ARF Family Proteins and Their Regulators and Effectors in Cancer Progression: A Therapeutic Perspective

Casalou

Ferreira

Barral

2020

Front. Cell Dev. Biol.

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The Adenosine diphosphate-Ribosylation Factor (ARF) family belongs to the RAS superfamily of small GTPases and is involved in a wide variety of physiological processes, such as cell proliferation, motility and differentiation by regulating membrane traffic and associating with the cytoskeleton. Like other members of the RAS superfamily, ARF family proteins are activated by Guanine nucleotide Exchange Factors (GEFs) and inactivated by GTPase-Activating Proteins (GAPs). When active, they bind effectors, which mediate downstream functions. Several studies have reported that cancer cells are able to subvert membrane traffic regulators to enhance migration and invasion. Indeed, members of the ARF family, including ARF-Like (ARL) proteins have been implicated in tumorigenesis and progression of several types of cancer. Here, we review the role of ARF family members, their GEFs/GAPs and effectors in tumorigenesis and cancer progression, highlighting the ones that can have a pro-oncogenic behavior or function as tumor suppressors. Moreover, we propose possible mechanisms and approaches to target these proteins, toward the development of novel therapeutic strategies to impair tumor progression.

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Regulation of the Sar1 GTPase Cycle Is Necessary for Large Cargo Secretion from the Endoplasmic Reticulum

Cited by 51 publications

References 98 publications

SAR1 paralogs differ biochemically in assembly of the COPII coat

SAR1 paralogs differ biochemically in assembly of the COPII coat

Proximity-dependent proteomics of theChlamydia trachomatisinclusion membrane reveals functional interactions with endoplasmic reticulum exit sites

The Role of ARF Family Proteins and Their Regulators and Effectors in Cancer Progression: A Therapeutic Perspective

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