Consequences of Rab GTPase dysfunction in genetic or acquired human diseases

Banworth, Marcellus J.; Li, Guangpu

doi:10.1080/21541248.2017.1397833

Cited by 56 publications

(39 citation statements)

References 434 publications

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“…Ras superfamily members contribute to oncogenesis, hereditary disorders, and infectious diseases when mutated or hyperactivated. 11 , 12 Mutant or hyperactivated Ras subfamily members are implicated in 30% of all human cancers because of their roles in cell signaling and are particularly prevalent in myeloid leukemia and pancreatic, lung, and colon carcinomas. 4 , 13 − 15 Cancer cell proliferation, motility, and invasiveness have been linked to cytoskeletal rearrangements caused by increased levels of activation of Rho GTPases through overexpression or mutations in their regulatory GEFs- or GAPs.…”

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confidence: 99%

“… 26 , 27 Missense mutations in Rab GTPases or associated regulatory proteins are associated with immune dysfunction, pigmentation, or neurological disorders due to impaired GTPase function and/or functional insufficiency. 12 , 20 , 28 Thus, Ras and Ras-related GTPases are important targets for the development of small molecule agonists to complement known antagonists. Such agonists will aid studies of disease mechanism and serve as scaffolds for future therapeutics.…”

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confidence: 99%

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Activation of Rho Family GTPases by Small Molecules

et al. 2018

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Ras and Ras-related small GTPases are key regulators of diverse cellular functions that impact cell growth, survival, motility, morphogenesis, and differentiation. They are important targets for studies of disease mechanisms as well as drug discovery. Here, we report the characterization of small molecule agonists of one or more of six Rho, Rab, and Ras family GTPases that were first identified through flow cytometry-based, multiplexed high-throughput screening of 200000 compounds. The activators were categorized into three distinct chemical families that are represented by three lead compounds having the highest activity. Virtual screening predicted additional compounds with potential GTPase activating properties. Secondary dose–response assays performed on compounds identified through these screens confirmed agonist activity of 43 compounds. While the lead and second most active small molecules acted as pan activators of multiple GTPase subfamilies, others showed partial selectivity for Ras and Rab proteins. The compounds did not stimulate nucleotide exchange by guanine nucleotide exchange factors and did not protect against GAP-stimulated GTP hydrolysis. The activating properties were caused by a reversible stabilization of the GTP-bound state and prolonged effector protein interactions. Notably, these compounds were active both in vitro and in cell-based assays, and small molecule-mediated changes in Rho GTPase activities were directly coupled to measurable changes in cytoskeletal rearrangements that dictate cell morphology.

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Activation of Rho Family GTPases by Small Molecules

et al. 2018

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“…( 27,35 ) These effectors are generally regulated by the Rab proteins that belong to a large family of small GTP‐binding proteins, which accomplish their functions by switching between an inactive GTP‐bound and an active GTP‐bound form. ( 27,28 ) Rab13 regulates ER‐Golgi trafficking, ( 36 ) and other Rab proteins such as Rab18 are involved in cellular processes including formations of inflammasome and autophagosome, lipid droplets turnover, and ER calcium homeostasis, ( 37,38 ) all of which could promote fatty liver injuries that are increasingly observed in patients with AIDS under anti‐HIV treatments. Although direct biochemical evidence for the enzyme‐substrate relation between RCE1 and Rab13 or Rab18 awaits further investigation, the observation that overexpression of Rab13 or Rab18 in PHHs not only mitigated the Golgi stress response but also partially rescued the liver cell from death injury supports the critical role of the RCE1‐Rab pathway in the anti‐HIV drug‐induced hepatotoxicity.…”

Section: Discussionmentioning

confidence: 99%

Ritonavir and Lopinavir Suppress RCE1 and CAAX Rab Proteins Sensitizing the Liver to Organelle Stress and Injury

Khalatbari¹,

Mishra²,

Han³

et al. 2020

Hepatol Commun

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Organelle stress and Liver injuries often occur in human immunodeficiency virus (HIV) infected patients underanti-HIV therapies, yet few molecular off-targets of anti-HIV drugs have been identified in the liver. Here, we found through total RNA sequencing that the transcription of a host protease Ras converting CAAX endopeptidase 1 (RCE1) was altered in HepG2 cells treated with anti-HIV protease inhibitors, ritonavir and lopinavir. Levels of RCE1 protein were inhibited in HepG2 and primary mouse hepatocytes and in the liver of mice treated with the anti-HIV drugs, which were accompanied with inhibition of two potential substrates of RCE1, small GTP binding protein Rab13 and Rab18, which are with a common CAAX motif and known to regulate the ER-Golgi traffic or lipogenesis. Neither Rce1 transcription nor RCE1 protein level was inhibited by Brefeldin A, which is known to interfere with the ER-Golgi traffic causing Golgi stress. Knocking down Rce1 with RNA interference increased ritonavir and lopinavir-induced cell death as well as expression of Golgi stress response markers, TFE3, HSP47 and GCP60, in both primary mouse hepatocytes and mouse liver, and deteriorated alcohol-induced alanine aminotransferase (ALT) and fatty liver injury in mice. In addition, overexpressing Rab13 or Rab18 in primary human hepatocytes reduced partially the anti-HIV drugs and alcohol-induced Golgi fragmentation, Golgi stress response, and cell death injury. Conclusion: We identified a mechanism linking a host protease and its substrates, small guanosine triphosphate-binding proteins, to the anti-HIV drug-induced Golgi dysfunction, organelle stress response, and fatty liver injury. (Hepatology Communications 2020;4:932-944).

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“…Studies on diseases associated with Rabs or Rab-interacting proteins have shed light on the important role of intracellular membrane trafficking in disease etiology. Marcellus J. Banworth and Guangpu Li [13] cover recent advances in the field with an emphasis on cellular mechanisms. Intracellular bacterial pathogens have evolved highly specialized mechanisms to enter and survive within their eukaryotic hosts, where they need to evade detection by the host immune system and to obtain nutrients and biosynthetic precursors.…”

Section: Rab Proteins and Pathologiesmentioning

confidence: 99%