9.A.78. The Retinal Degeneration B Protein (RdgB) Family RdgB catalyzes the transfer of phosphatidylinositol (PI) and phosphatidic acid (PA) between membranes (Garner et al. 2012). It may control the phosphatidylinositol concentration in transport vesicles from the subrhabdomeric cisternae (SRC) to the rhabdomere (Vihtelic et al. 1991) and may also function as a calcium transporter (Vihtelic et al. 1991). Eukaryotic proteins containing a phosphatidylinositol transfer (PITP) domain can be divided into two groups, one consisting of small soluble 35-kDa proteins and the other that are membrane- associated and show sequence similarities to the Drosophila retinal degeneration B (rdgB) protein. The rdgB protein consists of four domains, an amino terminal PITP domain, a Ca²⁺-binding domain, a transmembrane domain and a carboxyl terminal domain that interacts with the protein tyrosine kinase, PYK2. Three mammalian phosphatidylinositol transfer protein membrane-associated genes (PITPNM1, 2 and 3) with homology to Drosophila rdgB have been described and are expressed in the mammalian retina. The rdgB gene plays a critical role in the invertebrate phototransduction pathway, and homologous genes are considered as candidate genes for human eye diseases. Phylogenetic analysis indicates that the human genes arose by gene duplication that occurred very early in animal evolution (Ocaka et al. 2005). PITPNC1 links KRAS to MYC to prevent autophagy in lung and pancreatic cancer (Entrialgo-Cadierno et al. 2023).
References:
Amarilio, R., S. Ramachandran, H. Sabanay, and S. Lev. (2005). Differential regulation of endoplasmic reticulum structure through VAP-Nir protein interaction. J. Biol. Chem. 280: 5934-5944.
Entrialgo-Cadierno, R., C. Cueto-Ureña, C. Welch, I. Feliu, I. Macaya, L. Vera, X. Morales, S.V. Michelina, P. Scaparone, I. Lopez, E. Darbo, O. Erice, A. Vallejo, H. Moreno, A. Goñi-Salaverri, D. Lara-Astiaso, N. Halberg, I. Cortes-Dominguez, E. Guruceaga, C. Ambrogio, F. Lecanda, and S. Vicent. (2023). The phospholipid transporter PITPNC1 links KRAS to MYC to prevent autophagy in lung and pancreatic cancer. Mol Cancer 22: 86.
Fullwood, Y., M. dos Santos, and J.J. Hsuan. (1999). Cloning and characterization of a novel human phosphatidylinositol transfer protein, rdgBbeta. J. Biol. Chem. 274: 31553-31558.
Garner, K., A.N. Hunt, G. Koster, P. Somerharju, E. Groves, M. Li, P. Raghu, R. Holic, and S. Cockcroft. (2012). Phosphatidylinositol transfer protein, cytoplasmic 1 (PITPNC1) binds and transfers phosphatidic acid. J. Biol. Chem. 287: 32263-32276.
Hsu, C.C., C.Y. Wang, R.K. Manne, Z. Cai, V. Penugurti, R. Kant, L. Bai, B.S. Pan, T. Chen, Y.R. Chen, H.E. Wu, Y. Jin, H. Gu, C.Y. Li, and H.K. Lin. (2025). ALDH4A1 functions as an active component of the MPC complex maintaining mitochondrial pyruvate import for TCA cycle entry and tumour suppression. Nat. Cell Biol. 27: 847-862.
Lev, S., J. Hernandez, R. Martinez, A. Chen, G. Plowman, and J. Schlessinger. (1999). Identification of a novel family of targets of PYK2 related to Drosophila retinal degeneration B (rdgB) protein. Mol. Cell Biol. 19: 2278-2288.
Litvak, V., N. Dahan, S. Ramachandran, H. Sabanay, and S. Lev. (2005). Maintenance of the diacylglycerol level in the Golgi apparatus by the Nir2 protein is critical for Golgi secretory function. Nat. Cell Biol. 7: 225-234.
Litvak, V., R. Argov, N. Dahan, S. Ramachandran, R. Amarilio, A. Shainskaya, and S. Lev. (2004). Mitotic phosphorylation of the peripheral Golgi protein Nir2 by Cdk1 provides a docking mechanism for Plk1 and affects cytokinesis completion. Mol. Cell 14: 319-330.
Mishra, S., V. Manohar, S. Chandel, T. Manoj, S. Bhattacharya, N. Hegde, V.R. Nath, H. Krishnan, C. Wendling, T. Di Mattia, A. Martinet, P. Chimata, F. Alpy, and P. Raghu. (2024). A genetic screen to uncover mechanisms underlying lipid transfer protein function at membrane contact sites. Life Sci Alliance 7:.
Ocaka, L., C. Spalluto, D.I. Wilson, D.M. Hunt, and S. Halford. (2005). Chromosomal localization, genomic organization and evolution of the genes encoding human phosphatidylinositol transfer protein membrane-associated (PITPNM) 1, 2 and 3. Cytogenet Genome Res 108: 293-302.
Tian, D., V. Litvak, M. Toledo-Rodriguez, S. Carmon, and S. Lev. (2002). Nir2, a novel regulator of cell morphogenesis. Mol. Cell Biol. 22: 2650-2662.
Vihtelic, T.S., D.R. Hyde, and J.E. O'Tousa. (1991). Isolation and characterization of the Drosophila retinal degeneration B (rdgB) gene. Genetics 127: 761-768.
Examples:
TC#	Name	Organismal Type	Example
9.A.78.1.1	Membrane-associated phosphatidylinositol transfer protein 1, PITPNM1, of 1244 aas and possibly 8 TMSs in a 4 + 4 TMS arrangement. It catalyzes the transfer of phosphatidylinositol (PI) between membranes (Garner et al. 2012, Fullwood et al. 1999). It binds PI, phosphatidylcholine (PC) and phosphatidic acid (PA) with the binding affinity order of PI > PA > PC (Garner et al. 2012) and regulates RHOA activity while playing a role in cytoskeleton remodeling (Tian et al. 2002). It is necessary for normal completion of cytokinesis (Litvak et al. 2004) and plays a role in maintaining normal diacylglycerol levels in the Golgi apparatus (Litvak et al. 2005). It seems to be necessary for maintaining the normal structure of the endoplasmic reticulum and the Golgi apparatus (Amarilio et al. 2005) and is required for protein export from the endoplasmic reticulum and the Golgi (Litvak et al. 2005). It binds calcium ions (Lev et al. 1999).		PITPNM1 of Homo sapiens

9.A.78.1.2	Protein retinal degeneration B, RdgB, of 1259 aas, possibly with a central 8 TMSs unit in a 4 + 4 TMS arrangement. It catalyzes the transfer of phosphatidylinositol (PI) and phosphatidic acid (PA) between membranes (Garner et al. 2012). It may control the phosphatidylinositol concentration in transport vesicles from the subrhabdomeric cisternae (SRC) to the rhabdomere as well as functioning as a calcium transporter (Vihtelic et al. 1991). Lipid transfer proteins mediate the transfer of lipids between organelle membranes, and the loss of function of these proteins has been linked to neurodegeneration. In Drosophila photoreceptors, depletion of retinal degeneration B (RDGB), a phosphatidylinositol transfer protein, leads to defective phototransduction and retinal degeneration. RDGB is localized to membrane contact sites through the interaction of its FFAT motif with the ER integral protein VAP. To identify regulators of RDGB function in vivo, Mishra et al. 2024 depleted more than 300 VAP-interacting proteins and identified a set of 52 suppressors of rdgB. The molecular identity of these suppressors indicates a role of novel lipids in regulating RDGB function and of transcriptional and ubiquitination processes in mediating retinal degeneration in rdgB. The human homologs of several of these molecules have been implicated in neurodevelopmental diseases, underscoring the importance of VAP-mediated processes in these disorders.		*RdgB of Drosophila melanogaster* (Fruit fly)**

9.A.78.1.3	Phospholipase DDHD1 isoform X3 of 621 aas and possibly 4 C-terminal TMSs.		DDHD1 of Leptonychotes weddellii

9.A.78.1.4	Phospholipase DDHD2 isoform X5 of 732 aas and ? TMSs.		DDHD2.5 of Oryzias melastigma

9.A.78.1.5	Putative phosphatase of 995 aas and possibly 4 central TMSs.		Phosphatase of Colletotrichum viniferum

9.A.78.1.6	DDHD-domain-containing protein of 677 aas and possibly 4 central TMSs.		Possible phosphatase of Fragilariopsis cylindrus

9.A.78.1.7	*Phosphatidylinositol transfer protein, PITP, of 271 aas (Hsu et al.* 2025).**		PITP of Homo sapiens