A Role for Rac3 GTPase in the Regulation of Autophagy

Zhu, Wanlong; Hossain, Mohammad Sorowar; Guo, D.; Liu, Sen; Tong, Honglian; Khakpoor, Atefeh; Casey, Patrick J.; Wang, Mei

doi:10.1074/jbc.m111.280990

Cited by 33 publications

(28 citation statements)

References 44 publications

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“…14 On the other hand, we have found that RAC1 but not CDC42 is also involved in the regulation of the autophagic pathway, but it has an inhibitory role. Consistently, in a paper recently published by Zhu and collaborators 43 it has been demonstrated, using a siRNA approach, that RAC3 but not the RAC1 or RAC2 isoforms, has an inhibitory effect on autophagy. These differences in isoform requirement are likely due to the cell lines used.…”

Section: Discussionsupporting

confidence: 68%

The actin cytoskeleton participates in the early events of autophagosome formation upon starvation induced autophagy

Aguilera

Berón²,

Colombo³

2012

Autophagy

145

139

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Autophagy is a process by which cytoplasmic material is sequestered in a double-membrane vesicle destined for degradation. Nutrient deprivation stimulates the pathway and the number of autophagosomes in the cell increases in response to such stimulus. In the current report we have demonstrated that actin is necessary for starvation-mediated autophagy. When the actin cytoskeleton is depolymerized, the increase in autophagic vacuoles in response to the starvation stimulus was abolished without affecting maturation of remaining autophagosomes. In addition, actin filaments colocalized with ATG14, BECN1/Beclin1 and PtdIns3P-rich structures, and some of them have a typical omegasome shape stained with the double FYVE domain or ZFYVE1/DFCP1. In contrast, no major colocalization between actin and ULK1, ULK2, ATG5 or MAP1LC3/LC3 was observed. Taken together, our data indicate that actin has a role at very early stages of autophagosome formation linked to the PtdIns3P generation step. In addition, we have found that two members of the Rho family of proteins, RHOA and RAC1 have a regulatory function on starvation-mediated autophagy, but with opposite roles. Indeed, RHOA has an activatory role whereas Rac has an inhibitory one. We have also found that inhibition of the RHOA effector ROCK impaired the starvation-mediated autophagic response. We propose that actin participates in the initial membrane remodeling stage when cells require an enhanced rate of autophagosome formation, and this actin function would be tightly regulated by different members of the Rho family.

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Section: Discussionsupporting

confidence: 68%

The actin cytoskeleton participates in the early events of autophagosome formation upon starvation induced autophagy

Aguilera

Berón²,

Colombo³

2012

Autophagy

145

139

View full text Add to dashboard Cite

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“…We show here that Rac1 inhibition is essential for autophagic flux during starvation and potentially other stimuli (Zhu et al., 2011). Active Rac1 and LC3 compete for binding on neighboring domains in Armus.…”

Section: Discussionsupporting

confidence: 52%

The TBC/RabGAP Armus Coordinates Rac1 and Rab7 Functions during Autophagy

et al. 2013

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SummaryAutophagy is an evolutionarily conserved process that enables catabolic and degradative pathways. These pathways commonly depend on vesicular transport controlled by Rabs, small GTPases inactivated by TBC/RabGAPs. The Rac1 effector TBC/RabGAP Armus (TBC1D2A) is known to inhibit Rab7, a key regulator of lysosomal function. However, the precise coordination of signaling and intracellular trafficking that regulates autophagy is poorly understood. We find that overexpression of Armus induces the accumulation of enlarged autophagosomes, while Armus depletion significantly delays autophagic flux. Upon starvation-induced autophagy, Rab7 is transiently activated. This spatiotemporal regulation of Rab7 guanosine triphosphate/guanosine diphosphate cycling occurs by Armus recruitment to autophagosomes via interaction with LC3, a core autophagy regulator. Interestingly, autophagy potently inactivates Rac1. Active Rac1 competes with LC3 for interaction with Armus and thus prevents its appropriate recruitment to autophagosomes. The precise coordination between Rac1 and Rab7 activities during starvation suggests that Armus integrates autophagy with signaling and endocytic trafficking.

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“…Of the Rho family GTPases, Rac3 is implicated in regulating cell adhesion, growth, differentiation, and autophagy [38]. To date, little is known regarding the molecular regulation of Rac3 stability.…”

Section: Discussionmentioning

confidence: 99%

F-box protein complex FBXL19 regulates TGFβ1-induced E-cadherin down-regulation by mediating Rac3 ubiquitination and degradation

et al. 2014

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BackgroundRac3 is a small GTPase multifunctional protein that regulates cell adhesion, migration, and differentiation. It has been considered as an oncogene in breast cancer; however, its role in esophageal cancer and the regulation of its stability have not been studied. F-box proteins are major subunits within the Skp1-Cullin-1-F-box (SCF) E3 ubiquitin ligases that recognize particular substrates for ubiquitination and proteasomal degradation. Recently, we have shown that SCFFBXL19 targets Rac1 and RhoA, thus regulating Rac1 and RhoA ubiquitination and degradation. Here, we demonstrate the role of FBXL19 in the regulation of Rac3 site-specific ubiquitination and stability. Expression of TGFβ1 is associated with poor prognosis of esophageal cancer. TGFβ1 reduces tumor suppressor, E-cadherin, expression in various epithelial-derived cancers. Here we investigate the role of FBXL19-mediated Rac3 degradation in TGFβ1-induced E-cadherin down-regulation in esophageal cancer cells.MethodsFBXL19-regulated endogenous and over-expressed Rac3 stability were determined by immunoblotting and co-immunoprecipitation. Esophageal cancer cells (OE19 and OE33) were used to investigate TGFβ1-induced E-cadherin down-regulation by Immunoblotting and Immunostaining.ResultsOverexpression of FBXL19 decreased endogenous and over-expressed Rac3 expression by interacting and polyubiquitinating Rac3, while down-regulation of FBXL19 suppressed Rac3 degradation. Lysine166 within Rac3 was identified as an ubiquitination acceptor site. The FBXL19 variant with truncation at the N-terminus resulted in an increase in Rac3 degradation; however, the FBXL19 variant with truncation at the C-terminus lost its ability to interact with Rac3 and ubiquitinate Rac3 protein. Further, we found that Rac3 plays a critical role in TGFβ1-induced E-cadherin down-regulation in esophageal cancer cells. Over-expression of FBXL19 attenuated TGFβ1-induced E-cadherin down-regulation and esophageal cancer cells elongation phenotype.ConclusionsCollectively these data unveil that FBXL19 functions as an antagonist of Rac3 by regulating its stability and regulates the TGFβ1-induced E-cadherin down-regulation. This study will provide a new potential therapeutic strategy to regulate TGFβ1 signaling, thus suppressing esophageal tumorigenesis.

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A Role for Rac3 GTPase in the Regulation of Autophagy

Cited by 33 publications

References 44 publications

The actin cytoskeleton participates in the early events of autophagosome formation upon starvation induced autophagy

The actin cytoskeleton participates in the early events of autophagosome formation upon starvation induced autophagy

The TBC/RabGAP Armus Coordinates Rac1 and Rab7 Functions during Autophagy

F-box protein complex FBXL19 regulates TGFβ1-induced E-cadherin down-regulation by mediating Rac3 ubiquitination and degradation

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