3. A Critical Analysis of Shomron et al.'s Article (2021) and its Contribution to a New Model of ER Exit Site Formation

Introduction

The Endoplasmic Reticulum (ER) is a vital component of cells due to its involvement in protein synthesis, modification, and transport. Nevertheless, debates around transport to and from ER have persisted within cellular biology circles for decades. This has not only been limited to cargo exiting the ER but also on the argument between cisternal maturation and vesicular trafficking of cargo within the Golgi apparatus. In a bid to advance ER transport understanding further, Shomron et al. have introduced a new model of ER exit site mechanics.

Discussion

Critical Evaluation

Shomron et al.'s article investigates the conserved protein complex COPII's role in the formation of ER Exit Sites (ERES). Through novel findings, the study contributes to the emerging new model of ERES formation.

The authors conducted a comprehensive analysis of COPII localization, how it plays a role in ERES formation, and its interactions with other proteins involved in ERES assembly. The study's results highlight that COPII is a critical component of ERES formation. It also plays an essential role in maintaining the proper localization and function of other ERES proteins.

The authors further identify a new pathway for ERES formation. According to the paper, ER to ERES movement takes place through a COPII-coated membrane collar due to export cargo signal specific interactions mediating selective cargo concentration. The addition of COPII on the ER side of the membrane continuously replaces Sec12 and Sar1, causing cargo movement through the COPII collar membrane.

Overall, Shomron et al.'s article provides valuable insights into the complex processes involved in ERES formation. The findings of the study support the emerging new model for ERES formation, suggesting that ERES assembly involves multiple protein complex coordination and signaling pathways. Additionally, the results of the study are congruent with other recently published papers.

However, it is worth noting that the study has areas that require further consideration and study. For instance, the experiments took place in vitro using cell lines, and the results may not reflect the in vivo processes involved in ERES formation accurately. Furthermore, the study only focused on COPII's role in ERES assembly, and it may be helpful to explore other critical components of the ERES assembly pathway alongside COPII.

Current Model

The current model for ERES formation involves COPII-coated vesicles selectively transporting newly synthesized cargo upon leaving the ER. Ras-like GTPase Sar1 becomes activated by ER guanine nucleotide exchange factor (GEF) Sec12 to form Sar1-GTP and bind to the ER membrane. At activation, Sar1 changes conformation to expose an N-terminal amphipathic α-helix, allowing it to insert into the membrane. Sar1 then recruits coat proteins Sec23/24, followed by Sec13/31, inducing polymerization, budding, and vesicle pinching, leading to COPII-coated vesicle formation (Figure 1). These vesicles function exclusively in anterograde transport from the ER to the early Golgi. After vesicle fusion at the Golgi apparatus, the v-SNARE is exposed and can dock with partner t-SNAREs, permitting fusion. Finally, NSF and SNAPs are required for the release of the SNARE pairs.

Figure 1. Overview of COPII-Coated Vesicle Formation. Activation of an ARF family protein by a cognate GEF Sec12 (step I) leads to membrane recruitment of Sec23/24 heterodimer, forming the Sec23/24-Sar1 pre-budding complex (step II). Recruitment of Sec13/31 promotes coat polymerization, cargo selection, and membrane disruption, starting vesicle formation (step III). GTP hydrolysis triggers disassembly (step IV). Adapted from [7].

A new model for the formation of ER exit sites (ERES) is emerging in the scientific community. While other researchers in the US have proposed a similar conclusion, Shomron et al.'s paper provides crucial insights into the complex processes involved in ERES formation. The study's results suggest that the presence of a COPII collar prevents the formation of COPII coated vesicles, which instead package the cargo into an ERES vesicle. COPII's role in the recruitment, sorting, and transport of proteins from the ER is well-established.

Shomron et al. propose that COPII is stationary and stable at the ERES boundary, bound to a membrane rather than coating vesicles. This supports the new model of ERES formation, which hypothesizes that the ER generates contiguous lipid bilayers to form an elaborate tubular network for protein export, rather than just vesicles. This network extends from the ER to the Golgi apparatus and maintains a connection to the ER through a thin "neck" where COPII is situated.

Overall, the study presents a new pathway for ERES formation that proposes that export cargo signal-specific interactions result in ER to ERES movement through a COPII-coated membrane collar. The authors' work only focuses on COPII's role in ERES formation, and further investigation of other critical components of the pathway is necessary.

The results of Shomron et al.'s study align with other papers published recently, suggesting that ERES formation may involve an elaborate tubular network of contiguous lipid bilayers that transport proteins. The study opens new avenues for research to understand better and provide potential mechanisms into the complex processes involved in ERES formation. This multi-step process involves the coordinated actions of multiple protein complexes and signaling pathways.

In conclusion, the study by Shomron et al. is just one step towards understanding the complex mechanisms involved in ERES formation. With the emerging model proposing a new pathway for ERES formation, further research is necessary to investigate other crucial components of the pathway. The study's results support the idea of an elaborate tubular network of contiguous lipid bilayers, maintaining a connection between the ER and Golgi apparatus while providing potential mechanisms for ERES formation. Overall, the study presents a valuable contribution to the scientific community's research into understanding ERES formation.

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[6] Bi, Xiping et al. published a research paper titled “Structure of the Sec23/24-Sar1 pre-budding complex of the COPII vesicle coat” in the journal Nature in 2002. Their paper discusses the structural features of the COPII vesicle coat that is formed through the pre-budding complex of Sec23/24-Sar1. The paper can be accessed at doi:10.1038/nature01040.

[7] Bickford, Lincoln C et al. wrote a paper titled “A structural view of the COPII vesicle coat” that was published in the journal Current Opinion in Structural Biology in 2004. The paper provides a detailed explanation of the COPII vesicle coat from a structural perspective. Interested readers can access the paper at doi:10.1016/j.sbi.2004.02.002.

[8] Alberts B, Johnson A, Lewis J, et al. (2002) has published the fourth edition of the book “Molecular Biology of the Cell” in New York under the banner of Garland Science. The book discusses the transportation of proteins from the endoplasmic reticulum (ER) to the Golgi apparatus. The book can be accessed online at https://www.ncbi.nlm.nih.gov/books/NBK26941/.

[9] Malis, Y., Hirschberg, K., & Kaether, C. (2022) published a paper in the journal BioEssays titled “Hanging the coat on a collar: Same function but different localization and mechanism for COPII”. The paper discusses a protein known as COPII that forms coat on transport vesicles moving from one cellular compartment to another. The paper can be accessed at https://doi.org/10.1002/bies.202200064.

[10] Hariri, Hanaa et al. published a research paper titled “Insights into the mechanisms of membrane curvature and vesicle scission by the small GTPase Sar1 in the early secretory pathway” in the journal Journal of Molecular Biology in 2014. The paper provides a detailed explanation of the mechanisms of membrane curvature and vesicle scission by the small GTPase Sar1 while it plays a significant role in the early secretory pathway. Interested readers can access the paper at doi:10.1016/j.jmb.2014.08.023.

[11] Maeda, Miharu et al. (2017) wrote a paper titled “TANGO1 recruits Sec16 to coordinately organize ER exit sites for efficient secretion” that was published in the journal The Journal of Cell Biology. The paper explains how TANGO1 recruits Sec16 to efficiently coordinate the organization of endoplasmic reticulum (ER) exit sites for efficient secretion. Interested readers can read the paper at doi:10.1083/jcb.201703084.