The Rab family of small GTPases regulates intracellular membrane trafficking by orchestrating the biogenesis, transport, tethering, and fusion of membrane-bound organelles and vesicles. Like other small GTPases, Rabs cycle between two states, an active (GTP-loaded) state and an inactive (GDP-loaded) state, and their cycling is catalyzed by guanine nucleotide exchange factors (GEFs) and GTPase-activating proteins (GAPs). Because an active form of each Rab localizes on a specific organelle (or vesicle) and recruits various effector proteins to facilitate each step of membrane trafficking, knowing when and where Rabs are activated and what effectors Rabs recruit is crucial to understand their functions. Since the discovery of Rabs, they have been regarded as one of the central hubs for membrane trafficking, and numerous biochemical and genetic studies have revealed the mechanisms of Rab functions in recent years. The results of these studies have included the identification and characterization of novel GEFs, GAPs, and effectors, as well as post-translational modifications, for example, phosphorylation, of Rabs. Rab functions beyond the simple effector-recruiting model are also emerging. Furthermore, the recently developed CRISPR/Cas technology has enabled acceleration of knockout analyses in both animals and cultured cells and revealed previously unknown physiological roles of many Rabs. In this review article, we provide the most up-to-date and comprehensive lists of GEFs, GAPs, effectors, and knockout phenotypes of mammalian Rabs and discuss recent findings in regard to their regulation and functions.

https://febs.onlinelibrary.wiley.com/doi/pdf/10.1111/febs.15453

Rab family of small GTPases: an updated view on their regulation and functions.

Salmonella Typhimurium is an intracellular pathogen that causes gastroenteritis in humans. Aided by a battery of effector proteins, S. Typhimurium resides intracellularly in a specialized vesicle, called the Salmonella-containing vacuole (SCV) that utilizes the host endocytic vesicular transport pathway (VTP). Here, we probed the possible role of SUMOylation, a post-translation modification pathway, in SCV biology. Proteome analysis by complex mass-spectrometry (MS/MS) revealed a dramatically altered SUMO-proteome (SUMOylome) in S. Typhimurium-infected cells. RAB7, a component of VTP, was key among several crucial proteins identified in our study. Detailed MS/MS assays, in vitro SUMOylation assays and structural docking analysis revealed SUMOylation of RAB7 (RAB7A) specifically at lysine 175. A SUMOylation-deficient RAB7 mutant (RAB7K175R) displayed longer half-life, was beneficial to SCV dynamics and functionally deficient. Collectively, the data revealed that RAB7 SUMOylation blockade by S. Typhimurium ensures availability of long-lived but functionally compromised RAB7, which was beneficial to the pathogen. Overall, this SUMOylation-dependent switch of RAB7 controlled by S. Typhimurium is an unexpected mode of VTP pathway regulation, and unveils a mechanism of broad interest well beyond Salmonella-host crosstalk. This article has an associated First Person interview with the first author of the paper.

A SUMOylation dependent switch of Rab7 governs intracellular life and pathogenesis of Salmonella Typhimurium

Rab GTPases are master regulators of membrane trafficking in eukaryotic cells. Phosphorylation of Rab GTPases was characterized in the 1990s and there have been intermittent reports of its relevance to Rab functions. Phosphorylation as a regulatory mechanism has gained prominence through the identification of Rabs as physiological substrates of leucine-rich repeat kinase 2 (LRRK2). LRRK2 is a Ser/Thr kinase that is associated with inherited and sporadic forms of Parkinson disease. In recent years, numerous kinases and their associated signaling pathways have been identified that lead to phosphorylation of Rabs. These emerging studies suggest that serine/threonine and tyrosine phosphorylation of Rabs may be a widespread and under-appreciated mechanism for controlling their membrane trafficking functions. Here we survey current knowledge of Rab phosphorylation and discuss models for how this post-translational mechanism exerts control of membrane trafficking.

Phosphorylation of Rab GTPases in the regulation of membrane trafficking

The small GTPase, Rab7a, and the regulators of its GDP/GTP-binding status were shown to have roles in both endocytic membrane traffic and autophagy. Classically known to regulate endosomal retrograde transport and late endosome-lysosome fusion, earlier work has indicated a role for Rab7a in autophagosome-lysosome fusion as well as autolysosome maturation. However, as suggested by recent findings on PTEN-induced kinase 1 (PINK1)-Parkin-mediated mitophagy, Rab7a and its regulators are critical for the correct targeting of Atg9a-bearing vesicles to effect autophagosome formation around damaged mitochondria. This mitophagosome formation role for Rab7a is dependent on an intact Rab cycling process mediated by the Rab7a-specific guanine nucleotide exchange factor (GEF) and GTPase activating proteins (GAPs). Rab7a activity in this regard is also dependent on the retromer complex, as well as phosphorylation by the TRAF family-associated NF-κB activator binding kinase 1 (TBK1). Here, we discuss these recent findings and broadened perspectives on the role of the Rab7a network in PINK1-Parkin mediated mitophagy.

Rab7a and Mitophagosome Formation.

Rab GTPases play key roles in various cellular processes. They are essential, among other roles, to membrane trafficking and intracellular signaling events. Both trafficking and signaling events are crucial for proper embryonic development. Indeed, embryogenesis is a complex process in which cells respond to various signals and undergo dramatic changes in their shape, position, and function. Over the last few decades, cellular studies have highlighted the novel signaling roles played by Rab GTPases, while numerous studies have shed light on the important requirements of Rab proteins at various steps of embryonic development. In this review, we aimed to generate an overview of Rab contributions during animal embryogenesis. We first briefly summarize the involvement of Rabs in signaling events. We then extensively highlight the contribution of Rabs in shaping metazoan development and conclude with new approaches that will allow investigation of Rab functions in vivo.

https://www.mdpi.com/1422-0067/21/3/1064/pdf

Rabs in Signaling and Embryonic Development.

Tyrosine phosphorylation of Rab7 by Src kinase.

ABSTRACT Multi-satellite and Multi-Signal-to-Noise Ratio (SNR) types provide more basic data for the monitoring of sea level height by Global Navigation Satellite System Interferometric Reflectometry (GNSS-IR) technology. Few studies predict sea level height with high temporal resolution. This study proposes a theory based on GNSS-IR technology and Auto Regressive Integrated Moving Average (ARIMA) model. Taking the MAYG station as an example, the process of sea level height prediction and the determination of the best prediction scheme are shown. First, the sea level height monitored by the GNSS-IR technology is averaged hour by hour as the sea level height at the instantaneous moment. A linear interpolation method is used to compensate for the missing sea level time series. Then, the number of days to participate in the prediction of GNSS-IR sea level height and its forecast are selected for the experiment of predicting tide level. In the tide level prediction study from DOY125 to DOY153, the results of predicting the future 24 h, 48 h, and 72 h from one tide level period (29 days) illustrate that the accuracy of predicting the sea level height at 24 h is the best (R: 0.967, RMSE: 0.270 m, ME: −0.151 m), and the predicted tide level is highly consistent with the tide level measured at the tide gauge station. In addition, experiments reveal that the prediction accuracy gradually decreases with the increase of prediction time. This study verifies the feasibility of the hour-by-hour sea level prediction theory combined with the GNSS-IR technology and the ARIMA model. It proves that the theory can carry out continuous prediction of sea level, further promoting the breakthrough and transformation of GNSS-IR technology to the application level.

Hourly sea level height forecast based on GNSS-IR by using ARIMA model

The low-cost GNSS devices are more convenient, flexible, and can be used as the low-cost Global Navigation Satellite System interferometric reflectometry (GNSS-IR) sensors. In this study, the feasibility and performance of low-cost GNSS devices for the temporary sea level measurement are assessed, by jointly utilizing signal-to-noise ratio (SNR) data from an Android smartphone Redmi Note 9 Pro and a low-cost antenna BT560 connected to a CHCNAV P5 GNSS receiver, while another identical receiver equipped with a standard geodetic-quality antenna and a pressure tide gauge (TG) were placed nearby for comparison. 80-hours of SNR data from multiple GNSS constellations were collected and processed. First, the SNR data from the three devices are compared and analyzed. In most cases, the SNR data of low-cost antennas have longer and clearer oscillations. But they are maybe more vulnerable due to the manufacturing of antennas or positioning modules. Second, quality control and height rate correction are crucial to stable sea level measurement of low-cost GNSS devices. Finally, the performance of sea level measurement of multiple GNSS constellations, dual-frequency, and dual-antenna was also assessed. It is found that the low-cost GNSS devices could yield stable sea level measurements, and have a root-mean-square error (RMSE) of about 16 cm, of which the performance is equivalent to or even slightly better than standard geodetic-quality devices, making it a promising solution for the temporary TGs. 

Feasibility and performance evaluation of low-cost GNSS devices for sea level measurement based on GNSS-IR

As an essential part of the global water cycle, the effective detection of snow depth is of great significance to the study of climate change. Global navigation satellite system interferometric reflectometry (GNSS-IR) technology emerged as a new ground-based snow depth monitoring method. The principle is to invert the height of the reflection surface according to the signal-to-noise ratio (SNR) at a low elevation angle. However, the topographic relief in the reflection area of GNSS stations often dramatically impacts the accuracy of snow depth inversion. This study proposes a terrain tilt correction (TTC) algorithm based on different azimuth intervals to address it. Taking the P351 and P676 stations in the United States as examples, the snow depth inversion research of different systems is carried out. In the P351 station with gentle terrain, the TTC algorithm can maintain the stable accuracy. In the P676 station with steep terrain, the TTC algorithm can effectively compensate for the error caused by the landscape and significantly improve the accuracy of snow depth inversion. The experimental results of the two stations show that the snow depth inversion results of different systems after TTC are consistent with the in situ snow depth provided by the respective meteorological stations. Subsequently, a Helmert variance component estimation (HVCE) weighting algorithm is introduced for multisystem combinations based on different systems with different snow depth inversion accuracies, and the feasibility and stability of the combination strategy are investigated. Compared with the in situ snow depth, the correlation coefficient ( $R$ ) of the combined snow depth at the P351 station is 0.91, the root-mean-square error (RMSE) is 19.7 cm, and the mean error (ME) is −12.2 cm. The snow depth obtained by the combination of the multisystem at the P676 station has an $R$ of 0.95, an RMSE of 9.9 cm, and an ME of −4.9 cm. Compared with HVCE weighting before TTC, the RMSE is reduced by 53.3%, and the absolute value of ME is reduced by 74.2%. This study is not only of great significance for high-precision snow depth monitoring but also provides a necessary technical reference for further research on multisystem combined.

Improvement of Snow Depth Inversion Derived From Terrain Tilt Correction and Multi-GNSS Measurements Using the Helmert Variance Component Estimation

Snow depth retrieval by using robust estimation algorithm to perform Multi-SNR and Multi-system fusion in GNSS-IR

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