Phosphatidylinositol 3-Phosphatase Myotubularin-related Protein 6 (MTMR6) Is Regulated by Small GTPase Rab1B in the Early Secretory and Autophagic Pathways

Mochizuki, Yasuhiro; Ohashi, Riuko; Kawamura, Takeshi; Iwanari, Hiroko; Kodama, Tatsuhiko; Naito, Makoto; Hamakubo, Takao

doi:10.1074/jbc.m112.395087

Cited by 44 publications

(39 citation statements)

References 65 publications

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“…Although GEFs and GDIs are thought to be the predominant binding partners for GDPbound Rabs, other interacting proteins have been described. For instance, the GRAM domain of myotubularin-related protein 6 (MTMR6) interacts preferentially with GDP-bound Rab1b (44). Furthermore, protrudin interacts preferentially with GDP-bound Rab11 (45).…”

Section: Endogenous Rab13 Associates With Membranes Through Protein-pmentioning

confidence: 99%

Rab13 Traffics on Vesicles Independent of Prenylation

Ioannou

Girard

McPherson

2016

Journal of Biological Chemistry

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Rab GTPases are critical regulators of membrane trafficking. The canonical view is that Rabs are soluble in their inactive GDP-bound form, and only upon activation and conversion to their GTP-bound state are they anchored to membranes through membrane insertion of a C-terminal prenyl group. Here we demonstrate that C-terminal prenylation is not required for Rab13 to associate with and traffic on vesicles. Instead, inactive Rab13 appears to associate with vesicles via protein-protein interactions. Only following activation does Rab13 associate with the plasma membrane, presumably with insertion of the C-terminal prenyl group into the membrane.Rab GTPases control all aspects of membrane trafficking, ranging from vesicle formation and transport to tethering and fusion with the target membrane (1). The understanding of Rab regulation is thus critical for a full understanding of membrane trafficking. Furthermore, disturbances in Rab function are observed in several diseases. Notably, alterations in the levels or activity of Rab5, Rab35, Rab8, and Rab13 have been implicated in phenotypes associated with cancer (2-5).As for all small GTPases, Rabs cycle between an active GTPbound form and an inactive GDP-bound form. They are activated by guanine nucleotide exchange factors (GEFs) 3 that facilitate the exchange of GDP for GTP, and they are inactivated by GTPase-activating proteins, which enhance Rab-mediated hydrolysis of GTP to GDP. Furthermore, Rabs are posttranslationally modified by prenylation; that is, the covalent attachment of either a Cys-15 (farnesyl) or Cys-20 (geranylgeranyl) isoprenoid to cysteine residues at the carboxyl terminus (6). When the Rab is active, it associates with membranes with insertion of the prenyl group into the lipid bilayer, whereas effector molecules bind to the switch region (7). This allows the Rab to coordinate the function of the effector protein to the membrane compartment where it is anchored. When the Rab is inactive, it loses affinity for the effector molecules and is extracted from membrane by GDP dissociation inhibitors (GDIs) (8, 9). GDIs bind the hydrophobic prenyl group to prevent its reassociation with the membrane and keep the Rab soluble in the cytosol. Consistently, deletion or mutation of the C-terminal cysteine residues results in complete cytosolic localization of both Rab4 and Rab5 (10).Rabs are thought to associate with membranes only upon activation (11). However, it seems that at least some Rabs can associate with the membrane in their inactive GDP-bound form. For example, inactive Rab35 exists on the plasma membrane, whereas inactive Rab11 can be found on cytoplasmic vesicles (12, 13). Here we show that inactive Rab13, in the absence of prenylation, traffics on vesicles derived from recycling and late endosomal compartments. It appears that Rab13 associates with these vesicles as part of a protein complex. Experimental ProceduresAntibodies, DNA Constructs, and shRNA-Mouse monoclonal antibodies used were as follows: Rab8 and flotillin (BD Biosciences), Rab9 (A...

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Section: Endogenous Rab13 Associates With Membranes Through Protein-pmentioning

confidence: 99%

Rab13 Traffics on Vesicles Independent of Prenylation

Ioannou

Girard

McPherson

2016

Journal of Biological Chemistry

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“…RAB proteins cycle between an active GTP-bound state and an inactive GDPbound state and act by recruiting effector proteins to mediate trafficking between different compartments (Stenmark, 2009). RAB1 regulates vesicular transport between the ER and Golgi, and was recently found to be important for omegasome formation (Mochizuki et al, 2013). The yeast TRAPPIII complex acts as an autophagy-specific guanine nucleotide exchange factor (GEF) for Ypt1 (the yeast homolog of RAB1) (Lynch-Day et al, 2010).…”

Section: Tethering and Fusion Of Incoming Phagophore Membranesmentioning

confidence: 99%

Membrane dynamics in autophagosome biogenesis

Carlsson

Simonsen

2015

Journal of Cell Science

188

169

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Bilayered phospholipid membranes are vital to the organization of the living cell. Based on fundamental principles of polarity, membranes create borders allowing defined spaces to be encapsulated. This compartmentalization is a prerequisite for the complex functional design of the eukaryotic cell, yielding localities that can differ in composition and operation. During macroautophagy, cytoplasmic components become enclosed by a growing double bilayered membrane, which upon closure creates a separate compartment, the autophagosome. The autophagosome is then primed for fusion with endosomal and lysosomal compartments, leading to degradation of the captured material. A large number of proteins have been found to be essential for autophagy, but little is known about the specific lipids that constitute the autophagic membranes and the membrane modeling events that are responsible for regulation of autophagosome shape and size. In this Commentary, we review the recent progress in our understanding of the membrane shaping and remodeling events that are required at different steps of the autophagy pathway.This article is part of a Focus on Autophagosome biogenesis. For further reading, please see related articles: 'ERES: sites for autophagosome biogenesis and maturation?' by Jana SanchezWandelmer et al. (J. Cell Sci. 128,(185)(186)(187)(188)(189)(190)(191)(192) and 'WIPI proteins: essential PtdIns3P effectors at the nascent autophagosome' by Tassula Proikas-Cezanne et al. (J. Cell Sci. 128,(207)(208)(209)(210)(211)(212)(213)(214)(215)(216)(217).

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“…The association of Rab1 with the cytoplasmic surface of IC and cis-Golgi membranes, and its absence from the ER, has been demonstrated by EM Saraste et al, 1995;Satoh et al, 2003;Marie et al, 2012; Figure 2). The two Rab1 isoforms, Rab1A and RAB1B (93% homology), are recruited to IC membranes at ERES, show similar localizations by LM (Mochizuki et al, 2013; Figure 3(a)), but seem to play distinct roles in tubular and vesicular (long and short range) trafficking within the IC. Accordingly, live cell imaging and cell fractionation have shown that Rab1A mainly associates with IC tubules (Sannerud et al, 2006;Marie et al, 2009), while Rab1B interacts with GBF1 and evidently modulates COPI recruitment to globular IC domains Monetta et al, 2007;see below).…”

Section: Rab1 and Rab2mentioning

confidence: 99%

“…Visualization of IC dynamics using GFP-Rab1A showed that the pleiomorphic transport carriers arriving along MTs from the cell periphery do not move directly to cis-Golgi, but are targeted to the MTOC/centrosome that is normally positioned next to the Golgi ribbon. In cells displaying centrosome motility, for example, cells that are migrating or entering mitosis, the centrosome-targeted membranes can be resolved as a separate compartment, called the pericentrosomal IC (pcIC), which is distinct from the cis-Golgi-adjacent IC domain (Marie et al, , 2012Mochizuki et al, 2013; Figure 3(a)). Live imaging further showed that the separated pcIC and the Golgi communicate via tubular and globular carriers.…”

Section: Interconnected Membrane Systemmentioning

confidence: 99%