RUFY1 : FYVE-finger containing protein; Rab4a interacting protein; Rab4aip; Rabip4; RUN and FYVE domain-containing 1; ZFYVE12
RUFY2 : Denn; KIAA1537; LZ-FYVE; Rabip4R; RABIP4R; RUN and FYVE domain-containing 2; ZFYVE13
RUFY3 : RIPX; Rap2 interacting protein X; RUN and FYVE domain-containing 3; SINGAR1; Single axon-related 1; ZFYVE30
RUFY4 : RUN and FYVE domain-containing 4; ZFYVE31
Function of the RUN Domain on RUFY Family Proteins
The RUN domain consists of approximately 70 amino acids. Because RUN domains are frequently found in proteins involved in the regulation of Rab small GTPases, the RUN domain has been suggested to be involved in Rab-mediated cellular action. The RUN domain-containing proteins have been shown to promote endosomal fusion and are also significant for vesicular transport. In addition, the RUN domains appear to be required for localization to endosomal microdomains (Mari et al. 2001). Physical interaction between RUN proteins and filamentous materials has been confirmed by several biochemical experiments. Relationship among small GTPases, RUN proteins, and motor proteins may reflect a novel function for these proteins in the transport of vesicular cargoes within cells. For example, it has been reported that FYCO1 with a RUN domain works as an adapter linking autophagosomes to microtubule molecular motors and the Rab7, which is implicated in the phagosomal transport and fusion (Pankiv et al. 2010). A RUN domain of UNC-14 protein binds to the kinesin-1, a heterotetramer composed of kinesin heavy chain and kinesin light chain, and it regulates synaptic vesicle localization, which is predicted to play an important role in multiple Ras-like GTPase signaling pathways (Ogura and Goshima 2006). Because RUN domains are often found in proteins involved in the regulation of Rab family small GTPases, the RUN domain has been proposed to be involved in the Rab-mediated membrane trafficking. Accumulating data support the hypothesis that the RUN domain-containing proteins might be in charge of an interaction with a filamentous network linked to actin cytoskeleton and/or microtubules. There might be a collective role underlying the mechanism of the relationship of RUN domain to small GTPases and motor proteins. In addition, several downstream molecules of PI3K are involved in regulation of the membrane trafficking by networking with vesicle-associated RUN domain proteins such as RUFY proteins (Kitagishi and Matsuda 2013).
RUFY1, also known as RABIP4 (Rab4-interacting protein) or ZFYVE12 (Zinc finger FYVE domain-containing protein 12), is a 708 amino acid protein which localizes to the cytoplasm and/or the early endosomal membrane (Yang et al. 2002; He et al. 2009). RUFY1 has been identified as one of the downstream effectors of Etk protein kinase that is highly expressed in brain, lung, testis, and kidney. RUFY1 binds to PI3P-containing phospholipid vesicles and participates in early endosomal membrane trafficking (Yang et al. 2002). Downstream effects of PI3K signaling are facilitated by proteins containing a PI3P binding component designated by the FYVE finger domain. FYVE domain proteins are usually localized at the endosomes, then play an important role in endocytosis. Through the Src homology 2 (SH2) and Src homology 3 (SH3) domains of Etk, the Etk interacts with RUFY1, then, phosphorylates certain Tyr-residues of RUFY1, which is essential for the endosomal localization (Yang et al. 2002). The Etk plays an essential role in the regulation of endocytosis as a downstream effector of PI3K. Two coiled-coil domains also regulate endosomal localization of RUFY1 (Mari et al. 2001). Accordingly, the PI3K inhibitor wortmannin blocks the endosomal localization of RUFY1 (Mari et al. 2001). Rab14 engages in a GTP-dependent interaction with RUFY1 (Yamamoto et al. 2010). The active Rab14 controls RUFY1 recruitment onto endosomal membranes, and Rab4 allows the endosomal fusion (Yamamoto et al. 2010). The Rab14 seems to be a principal factor of RUFY1 recruitment to the endosomes, and the FYVE domain may assist RUFY1 targeting to PI3P-enriched early endosomes (Yamamoto et al. 2010). Both Rab14 and RUFY1 are involved in Rab4-dependent recycling endosome. Enlargement of early endosomes mediated by RUFY1 requires the interaction with Rab4. The RUFY1 is also present in the sorting endosomes, which would provide directional trafficking way from the recycling endosomes to the sorting endosomes. In addition, RUFY1 can modify the kinetic parameters of Glut1 protein recycling (Cormont et al. 2001). RUFY1 may have a role in regulating lysosome positioning through an interorganellar pathway (Ivan et al. 2012).
RUFY2, also known as RABIP4R (Rab4-interacting protein related) or ZFYVE13 (Zinc finger FYVE domain-containing protein 13), contains a RUN domain and a carboxyl terminal FYVE zinc finger, separated by two coiled-coil domains. RUFY2 is expressed in brain, lung, and testis localizing to the cellular nucleus. RUFY2 as well as RUFY1 interacts with the Etk that is a tyrosine kinase involved in regulation of various cellular processes. The carboxyl domain of RUFY2 binds to negative form of Rab33A. Transcriptomic data of a miRNA dosage-sensitive gene have revealed significant associations in a subset of genes such as RUFY2 (Bofill-De Ros et al. 2015). In addition, the RUFY2-RET in lung cancer has been identified as new therapeutically important gene fusions (Zheng et al. 2014). However, little is known about the precise intracellular functions as poorly characterized for RUFY2.
RUN domain-containing proteins might be responsible for an interaction with a filamentous network linked to actin cytoskeleton and/or microtubules. In addition, several downstream molecules of PI3K are involved in the regulation of membrane trafficking by interacting with vesicle-associated RUFY family proteins, which may be activated in some of the cytoskeletal elements. The localization of RUFY proteins during membrane trafficking seems to be extremely dynamic. RUFY family consists of four members of RUFY proteins. RUFY1 binds to PI3P-containing phospholipid vesicles and participates in early endosomal membrane trafficking. RUFY2 as well as RUFY1 interacts with the Etk that is a tyrosine kinase involved in regulation of various cellular processes. RUFY3 may ensure the strength of neuronal cell polarity by suppressing formation of surplus axons. Furthermore, RUFY3 expression is correlated with tumor progression. RUFY4 may be a positive regulator of autophagy under specific immunological conditions. Interpreting the precise mechanisms involved in these processes will provide new insight into the physiological roles of the interesting proteins in regulating cellular functions. It is anticipated that future studies would address to get a better knowledge of the potential partners and novel roles of the RUFY proteins.
- Terawaki S, Camosseto V, Prete F, Wenger T, Papadopoulos A, Rondeau C, Combes A, Rodriguez Rodrigues C, Vu Manh TP, Fallet M, English L, Santamaria R, Soares AR, Weil T, Hammad H, Desjardins M, Gorvel JP, Santos MA, Gatti E, Pierre P. RUN and FYVE domain-containing protein 4 enhances autophagy and lysosome tethering in response to Interleukin-4. J Cell Biol. 2015;210:1133–52.PubMedPubMedCentralCrossRefGoogle Scholar