8.A.136. The Alpha/Beta-Arrestin (ARRB) Family β-arrestins function in the desensitization of seven membrane spanning receptors (7MSRs, GPCRs, TC# 9.A.14), especially in the endocytosis and signaling of these receptors (Magalhaes et al. 2012). These functions reflect the ability of the beta-arrestins to bind signaling and endocytic elements, often in an agonist-dependent fashion (Lefkowitz and Whalen 2004). One system leads to MAP kinase activation via beta-arrestin-mediated scaffolding of these pathways in a receptor-dependent fashion. The beta-arrestins are also found to be involved in the regulation of novel receptor systems, such as Frizzled and TGFbeta receptors as well as certain transporters such as ion channels and carriers (i.e., SLC9A5; the sodium/hydrogen exchanger, NHE5 (TC# 2.A.36.1.16). β-arrestin-1 acts as a scaffold for ADGRG2/CFTR complex formation in apical membranes, whereas specific residues of ADGRG2 confer coupling specificity for different G protein subtypes, the specificity of which is critical for male fertility (Zhang et al. 2018). Opioid receptors signal through two kinds of downstream partners, G-proteins and β-arrestins. Many side effects of opioid use are mediated by β-arrestins, and therefore, opioids that signal through G-proteins are preferred for treating pain. Ko et al. 2021 found that β-arrestin-based drugs can be used to treat fear and anxiety. There are distinct but overlapping functions for β-arrestin isoform. Loss of β-arrestins can cause a Warberg effect and prevent progesterone-induced rapid proteasomal degradation of progesterone receptor membrane component 1 (Sabbir et al. 2021). β-arrestins that regulate agonist-mediated desensitization and integration of signaling by transmembrane receptors, may be involved in the endothelial cell response to shear stress. In fact, endothelial β-arrestins are key transducers of ciliary mechanotransduction that play a central role in shear signaling and contribute to vascular development (Park et al. 2022). An ancient family of arrestin-fold proteins, termed alpha-arrestins, have conserved roles in regulating nutrient transporter trafficking and cellular metabolism as adaptor proteins. One alpha-arrestin, TXNIP (thioredoxin-interacting protein; TXNIP, TC# 8.A.136.1.14), is known to regulate myocardial glucose uptake as well as other transporters (Nakayama et al. 2022). β-arrestins are multifunctional proteins involved in signaling and regulation of seven transmembrane receptors (7TMRs), and their interaction is driven primarily by agonist-induced receptor activation and phosphorylation (Maharana et al. 2024). Plasma membrane transporters play pivotal roles in the import of nutrients, including sugars, amino acids, nucleobases, carboxylic acids, and metal ions, that surround fungal cells. The selective removal of these transporters by endocytosis is one of the most important regulatory mechanisms that ensures a rapid adaptation of cells to the changing environment (e.g., nutrient fluctuations or different stresses). At the heart of this mechanism lies a network of proteins that includes the arrestin-related trafficking adaptors (ARTs) which link the ubiquitin ligase Rsp5 to nutrient transporters and endocytic factors (Barata-Antunes et al. 2021). Transporter conformational changes, as well as dynamic interactions between its cytosolic termini/loops and with lipids of the plasma membrane, are also critical during the endocytic process. Barata-Antunes et al. 2021 reviewed the current knowledge and recent findings on the molecular mechanisms involved in nutrient transporter endocytosis, both in the budding yeast Saccharomyces cerevisiae and in some species of the filamentous fungus Aspergillus.
References:
Barata-Antunes, C., R. Alves, G. Talaia, M. Casal, H. Gerós, R. Mans, and S. Paiva. (2021). Endocytosis of nutrient transporters in fungi: The ART of connecting signaling and trafficking. Comput Struct Biotechnol J 19: 1713-1737.
Carroll, S.H., E. Zhang, B.F. Wang, K.B. LeClair, A. Rahman, D.E. Cohen, J. Plutzky, P. Patwari, and R.T. Lee. (2017). Adipocyte arrestin domain-containing 3 protein (Arrdc3) regulates uncoupling protein 1 (Ucp1) expression in white adipose independently of canonical changes in β-adrenergic receptor signaling. PLoS One 12: e0173823.
Chen, W., N. Li, T. Chen, Y. Han, C. Li, Y. Wang, W. He, L. Zhang, T. Wan, and X. Cao. (2005). The lysosome-associated apoptosis-inducing protein containing the pleckstrin homology (PH) and FYVE domains (LAPF), representative of a novel family of PH and FYVE domain-containing proteins, induces caspase-independent apoptosis via the lysosomal-mitochondrial pathway. J. Biol. Chem. 280: 40985-40995.
Gupta, M.K., M.L. Mohan, and S.V. Naga Prasad. (2018). G Protein-Coupled Receptor Resensitization Paradigms. Int Rev Cell Mol Biol 339: 63-91.
Han, S.O., R.P. Kommaddi, and S.K. Shenoy. (2013). Distinct roles for β-arrestin2 and arrestin-domain-containing proteins in β2 adrenergic receptor trafficking. EMBO Rep 14: 164-171.
Jeong, H., S. Clark, A. Goehring, S. Dehghani-Ghahnaviyeh, A. Rasouli, E. Tajkhorshid, and E. Gouaux. (2022). Structures of the TMC-1 complex illuminate mechanosensory transduction. Nature 610: 796-803.
Jiang, N., J. Liu, C. Guan, C. Ma, J. An, and X. Tang. (2022). Thioredoxin-interacting protein: A new therapeutic target in bone metabolism disorders? Front Immunol 13: 955128.
Kazan, J.M., G. Desrochers, C.E. Martin, H. Jeong, D. Kharitidi, P.M. Apaja, A. Roldan, N. St Denis, A.C. Gingras, G.L. Lukacs, and A. Pause. (2021). Endofin is required for HD-PTP and ESCRT-0 interdependent endosomal sorting of ubiquitinated transmembrane cargoes. iScience 24: 103274.
Ko, M.J., T. Chiang, A.A. Mukadam, G.E. Mulia, A.M. Gutridge, A. Lin, J.A. Chester, and R.M. van Rijn. (2021). β-Arrestin-dependent ERK signaling reduces anxiety-like and conditioned fear-related behaviors in mice. Sci Signal 14:.
Lefkowitz, R.J. and E.J. Whalen. (2004). β-arrestins: traffic cops of cell signaling. Curr. Opin. Cell Biol. 16: 162-168.
Magalhaes, A.C., H. Dunn, and S.S. Ferguson. (2012). Regulation of GPCR activity, trafficking and localization by GPCR-interacting proteins. Br J Pharmacol 165: 1717-1736.
Maharana, J., F.K. Sano, P. Sarma, M.K. Yadav, L. Duan, T.M. Stepniewski, M. Chaturvedi, A. Ranjan, V. Singh, S. Saha, G. Mahajan, M. Chami, W. Shihoya, J. Selent, K.Y. Chung, R. Banerjee, O. Nureki, and A.K. Shukla. (2024). Molecular insights into atypical modes of β-arrestin interaction with seven transmembrane receptors. Science 383: 101-108.
Nabhan, J.F., H. Pan, and Q. Lu. (2010). Arrestin domain-containing protein 3 recruits the NEDD4 E3 ligase to mediate ubiquitination of the beta2-adrenergic receptor. EMBO Rep 11: 605-611.
Nakayama, Y., N. Mukai, G. Kreitzer, P. Patwari, and J. Yoshioka. (2022). Interaction of ARRDC4 With GLUT1 Mediates Metabolic Stress in the Ischemic Heart. Circ Res 131: 510-527.
Park, S., Z. Ma, G. Zarkada, I. Papangeli, S. Paluri, N. Nazo, F. Rivera-Molina, D. Toomre, S. Rajagopal, and H.J. Chun. (2022). Endothelial β-arrestins regulate mechanotransduction by the type II bone morphogenetic protein receptor in primary cilia. Pulm Circ 12: e12167.
Patwari, P., V. Emilsson, E.E. Schadt, W.A. Chutkow, S. Lee, A. Marsili, Y. Zhang, R. Dobrin, D.E. Cohen, P.R. Larsen, A.M. Zavacki, L.G. Fong, S.G. Young, and R.T. Lee. (2011). The arrestin domain-containing 3 protein regulates body mass and energy expenditure. Cell Metab 14: 671-683.
Sabbir, M.G., A. Inoue, C.G. Taylor, and P. Zahradka. (2021). Loss of β-Arrestins or six Gα proteins in HEK293 cells caused Warburg effect and prevented progesterone-induced rapid proteasomal degradation of progesterone receptor membrane component 1. J Steroid Biochem Mol Biol 214: 105995.
Seet, L.F. and W. Hong. (2001). Endofin, an endosomal FYVE domain protein. J. Biol. Chem. 276: 42445-42454.
Seet, L.F., N. Liu, B.J. Hanson, and W. Hong. (2004). Endofin recruits TOM1 to endosomes. J. Biol. Chem. 279: 4670-4679.
Shi, E., X. Zhou, D. Li, Y. Zhang, J. Yuan, and J. Zou. (2019). β-Arrestin2 regulates the rapid component of delayed rectifier K⁺ currents and cardiac action potential of guinea pig cardiomyocytes after adrenergic stimulation. Cell Mol Biol (Noisy-le-grand) 65: 132-137.
Tan, K.W., V. Nähse, C. Campsteijn, A. Brech, K.O. Schink, and H. Stenmark. (2021). JIP4 is recruited by the phosphoinositide-binding protein Phafin2 to promote recycling tubules on macropinosomes. J Cell Sci 134:.
Waldhart, A.N., K.H. Lau, H. Dykstra, T. Avequin, and N. Wu. (2023). Optimal HSF1 activation in response to acute cold stress in BAT requires nuclear TXNIP. iScience 26: 106538.
Zhang, D.L., Y.J. Sun, M.L. Ma, Y.J. Wang, H. Lin, R.R. Li, Z.L. Liang, Y. Gao, Z. Yang, D.F. He, A. Lin, H. Mo, Y.J. Lu, M.J. Li, W. Kong, K.Y. Chung, F. Yi, J.Y. Li, Y.Y. Qin, J. Li, A.R.B. Thomsen, A.W. Kahsai, Z.J. Chen, Z.G. Xu, M. Liu, D. Li, X. Yu, and J.P. Sun. (2018). Gq activity- and β-arrestin-1 scaffolding-mediated ADGRG2/CFTR coupling are required for male fertility. Elife 7:.
Examples:
TC#	Name	Organismal Type	Example
8.A.136.1.1	β-arrestin, ARRB1, ARR1, of 418 aas. It functions in regulating agonist-mediated G-protein coupled receptor (GPCR) signaling by mediating both receptor desensitization and resensitization processes. activated GPCR undergoes inactivation or desensitization by phosphorylation and binding of β-arrestin resulting in diminution of downstream signals. The desensitized GPCRs are internalized into endosomes, wherein they undergo dephosphorylation or resensitization by a protein phosphatase to be recycled back to the cell membrane as a naïve GPCR (Gupta et al. 2018). It also controls the locations and activities of certain transport proteins (see family description).		β-arrestin of Homo sapiens

8.A.136.1.10	Arrestin domain-containing protein 3 of 484 aas		Arrestin 3 of Stomoxys calcitrans

8.A.136.1.11	Arrestin domain containing protein, ARRDC3, of 414 aas. It is an adapter protein that plays a role in regulating cell-surface expression of adrenergic receptors and other G protein-coupled receptors (Patwari et al. 2011, Han et al. 2013). It also plays a role in NEDD4-mediated ubiquitination and endocytosis af activated ADRB2 and subsequent ADRB2 degradation, and may recruit NEDD4 to ADRB2 (Nabhan et al. 2010). It also regulates uncoupling protein 1 (Ucp1; TC# 2.A.29.3.2) expression in adipose tissue (Carroll et al. 2017).		ARRDC3 of Homo sapiens

8.A.136.1.12	Pleckstrin homology domain-containing family F member 1, PLEKHF1 oe Phafin2, of 279 aas and 1 or 2 N-terminal TMSs. It may induce apoptosis through the lysosomal-mitochondrial pathway. It also translocates to the lysosome, initiating the permeabilization of lysosomal membrane and resulting in the release of CTSD and CTSL to the cytoplasm. It triggers the caspase-independent apoptosis by altering mitochondrial membrane permeabilization (MMP) resulting in the release of PDCD8 (Chen et al. 2005). JIP4 and Phafin2 are components of a tubular recycling pathway that operates from macropinosomes (Tan et al. 2021).		Phafin2 of Homo sapiens

8.A.136.1.13	Endofin (Zinc finger FYVE domain-containing protein 16, ZFYVE16, also called the endosome-associated FYVE domain protein) (Seet and Hong 2001). It has a small central domain homologous to other members of this family. It may be involved in regulating membrane trafficking in the endosomal pathway. Overexpression induces endosome aggregation. It is required to target TOM1 to endosomes (Seet et al. 2004). It has phosphatidyl inositol and metal binding capabilities. It is required for HD-PTP and ESCRT-0 (TC# 3.A.31) interdependent endosomal sorting of ubiquitinated transmembrane cargoes (Kazan et al. 2021).		Endofin of Homo sapiens

8.A.136.1.14	Thioredoxin-interacting protein (TXNIP), also known as thioredoxin-binding protein-2, is a member of the α-arrestin protein family and is regulated by several cellular stress factors. It is a 391 aa protein possibly with two TMSs, one near the N-terminus and one between residues 260 and 300. TXNIP overexpression coupled with thioredoxin inhibits its antioxidant functions, thereby increasing oxidative stress (Jiang et al. 2022). TXNIP is directly involved in inflammatory activation by interacting with Nod-like receptor protein 3 inflammasomes. Bone metabolic disorders are associated with aging, oxidative stress, and inflammation. They are characterized by an imbalance between bone formation involving osteoblasts and bone resorption by osteoclasts, and by chondrocyte destruction. The role of TXNIP in bone metabolic diseases has been extensively investigated. Jiang et al. 2022 discussed the roles of TXNIP in the regulatory mechanisms of transcription and protein levels and summarized its involvement in bone metabolic disorders such as osteoporosis, osteoarthritis, and rheumatoid arthritis. TXNIP is expressed in osteoblasts, osteoclasts, and chondrocytes, and it affects the differentiation and functioning of skeletal cells through both redox-dependent and redox-independent regulatory mechanisms (Jiang et al. 2022). It activates HSF1 (heat shock factor 1) in Brown adipose tissue (Waldhart et al. 2023).		TXNIP of Homo sapiens

8.A.136.1.15	ARRestin Domain protein, ARRD-6 of 442 aas and 0 or 1 TMS. This protein includes a single arrestin-like protein, arrestin domain protein-6 (ARRD-6), bound to a CALM-1 subunit in the TMC-1 complex (see TC# 1.A.17.4.7) (Jeong et al. 2022).		ARRD-6 of Caenorhabditis elegans

8.A.136.1.2	*Arrestin-2, ARRB2, ARR2, ARB2 of 421 aas. See family description for functions. β-arrestin2 regulates the cardiac hERG/IKr potassium channel (TC# 1.A.1.20.1; Shi et al.* 2019).**		ARRB2 of Homo sapiens

8.A.136.1.3	Arrestin domain-containing protein 3-like of 423 aas.		*Arrestin of Carassius auratus* (goldfish)**

8.A.136.1.4	Uncharacterized protein of 555 aas		*UP of Protopolystoma xenopodis* (roundworm)**

8.A.136.1.5	Uncharacterized protein of 638 aas		UP of Taenia asiatica

8.A.136.1.6	Uncharacterized protein of 690 aas		UP of Periconia macrospinosa

8.A.136.1.7	Uncharacterized protein of 457 aas		UP of Sphaeroforma arctica

8.A.136.1.8	Uncharacterized protein of 599 aas		UP of Dictyostelium purpureum

8.A.136.1.9	Arrestin-1 of 776 aas		Arrestin-1 of Echinococcus granulosus