PACS1

Summary

Gene Symbol: PACS1
Description: phosphofurin acidic cluster sorting protein 1
Alias: MRD17, SHMS, phosphofurin acidic cluster sorting protein 1, PACS-1, cytosolic sorting protein PACS-1
Species: human
Products:     PACS1

Top Publications

  1. Wan L, Molloy S, Thomas L, Liu G, Xiang Y, Rybak S, et al. PACS-1 defines a novel gene family of cytosolic sorting proteins required for trans-Golgi network localization. Cell. 1998;94:205-16 pubmed
    ..Cell-free assays indicate TGN localization of furin is directed by a PACS-1-mediated retrieval step. Together, these findings explain a mechanism by which membrane proteins in mammalian cells are localized to the TGN. ..
  2. Schermer B, Höpker K, Omran H, Ghenoiu C, Fliegauf M, Fekete A, et al. Phosphorylation by casein kinase 2 induces PACS-1 binding of nephrocystin and targeting to cilia. EMBO J. 2005;24:4415-24 pubmed
    ..Inhibition of CK2 activity abrogates this interaction and results in the loss of correct nephrocystin targeting. These data suggest that CK2-dependent transport processes represent a novel pathway of targeting proteins to the cilia. ..
  3. Piguet V, Wan L, Borel C, Mangasarian A, Demaurex N, Thomas G, et al. HIV-1 Nef protein binds to the cellular protein PACS-1 to downregulate class I major histocompatibility complexes. Nat Cell Biol. 2000;2:163-7 pubmed
    ..These results support a model in which Nef relocalizes MHC-I by acting as a connector between MHC-I's cytoplasmic tail and the PACS-1-dependent protein-sorting pathway. ..
  4. Crump C, Xiang Y, Thomas L, Gu F, Austin C, Tooze S, et al. PACS-1 binding to adaptors is required for acidic cluster motif-mediated protein traffic. EMBO J. 2001;20:2191-201 pubmed
    ..These studies demonstrate the requirement for PACS-1 interactions with adaptor proteins in multiple processes, including secretory granule biogenesis and HIV-1 pathogenesis. ..
  5. Williams M, Roeth J, Kasper M, Fleis R, Przybycin C, Collins K. Direct binding of human immunodeficiency virus type 1 Nef to the major histocompatibility complex class I (MHC-I) cytoplasmic tail disrupts MHC-I trafficking. J Virol. 2002;76:12173-84 pubmed
    ..In addition, they provide the first direct evidence indicating that Nef functions as an adaptor molecule able to link MHC-I to cellular trafficking proteins. ..
  6. Blagoveshchenskaya A, Thomas L, Feliciangeli S, Hung C, Thomas G. HIV-1 Nef downregulates MHC-I by a PACS-1- and PI3K-regulated ARF6 endocytic pathway. Cell. 2002;111:853-66 pubmed
    ..These data provide new insights into the cellular basis of HIV-1 immunoevasion. ..
  7. Dikeakos J, Atkins K, Thomas L, Emert Sedlak L, Byeon I, Jung J, et al. Small molecule inhibition of HIV-1-induced MHC-I down-regulation identifies a temporally regulated switch in Nef action. Mol Biol Cell. 2010;21:3279-92 pubmed publisher
    ..Together, these studies resolve the seemingly controversial models that describe Nef-induced MHC-I down-regulation and provide new insights into the mechanism of Nef action. ..
  8. Roeth J, Williams M, Kasper M, Filzen T, Collins K. HIV-1 Nef disrupts MHC-I trafficking by recruiting AP-1 to the MHC-I cytoplasmic tail. J Cell Biol. 2004;167:903-13 pubmed
    ..In sum, our evidence suggests that binding of AP-1 to the Nef-MHC-I complex is an important step required for inhibition of antigen presentation by HIV. ..
  9. Scott G, Fei H, Thomas L, Medigeshi G, Thomas G. A PACS-1, GGA3 and CK2 complex regulates CI-MPR trafficking. EMBO J. 2006;25:4423-35 pubmed
    ..Our results identify a CK2-controlled cascade regulating hydrolase trafficking and sorting of itinerant proteins in the TGN/endosomal system. ..

More Information

Publications37

  1. Jenkins P, Zhang L, Thomas G, Martens J. PACS-1 mediates phosphorylation-dependent ciliary trafficking of the cyclic-nucleotide-gated channel in olfactory sensory neurons. J Neurosci. 2009;29:10541-51 pubmed publisher
    ..These results provide a mechanism for the subunit-dependent ciliary trafficking of the CNG channel and offer insight into the mechanisms of ciliary transport...
  2. Hung C, Thomas L, Ruby C, Atkins K, Morris N, Knight Z, et al. HIV-1 Nef assembles a Src family kinase-ZAP-70/Syk-PI3K cascade to downregulate cell-surface MHC-I. Cell Host Microbe. 2007;1:121-33 pubmed
    ..The discovery of this Nef-SFK-ZAP-70/Syk-PI3K signaling pathway explains the hierarchal role of the Nef motifs in effecting immunoevasion. ..
  3. Köttgen M, Benzing T, Simmen T, Tauber R, Buchholz B, Feliciangeli S, et al. Trafficking of TRPP2 by PACS proteins represents a novel mechanism of ion channel regulation. EMBO J. 2005;24:705-16 pubmed
    ..Furthermore, PACS proteins may represent a novel molecular mechanism for ion channel trafficking, directing acidic cluster-containing ion channels to distinct subcellular compartments. ..
  4. Sachan V, Lodge R, Mihara K, Hamelin J, Power C, Gelman B, et al. HIV-induced neuroinflammation: impact of PAR1 and PAR2 processing by Furin. Cell Death Differ. 2019;: pubmed publisher
    ..proteins, likely due to the intermediary trafficking role of phospho-Furin acidic cluster sorting protein 1 (PACS1)...
  5. van der Donk R, Jansen S, Schuurs Hoeijmakers J, Koolen D, Goltstein L, Hoischen A, et al. Next-generation phenotyping using computer vision algorithms in rare genomic neurodevelopmental disorders. Genet Med. 2018;: pubmed publisher
    ..Facial features were extracted from photos of ID patients harboring a pathogenic variant in three novel ID genes (PACS1, PPM1D, and PHIP) using algorithms that model human facial dysmorphism, and facial recognition...
  6. Brasacchio D, Busuttil R, Noori T, Johnstone R, Boussioutas A, Trapani J. Down-regulation of a pro-apoptotic pathway regulated by PCAF/ADA3 in early stage gastric cancer. Cell Death Dis. 2018;9:442 pubmed publisher
    ..pathway to apoptosis via epigenetic regulation of phosphofurin acidic cluster sorting proteins 1 and 2 (PACS1, PACS2), we analyzed PCAF, ADA3, and PACS1/2 expression in 99 patient-matched surgical samples ranging from normal ..
  7. Olson H, Jean Marçais N, Yang E, Heron D, Tatton Brown K, van der Zwaag P, et al. A Recurrent De Novo PACS2 Heterozygous Missense Variant Causes Neonatal-Onset Developmental Epileptic Encephalopathy, Facial Dysmorphism, and Cerebellar Dysgenesis. Am J Hum Genet. 2018;102:995-1007 pubmed publisher
    ..PACS2 is an important PACS1 paralog and encodes a multifunctional sorting protein involved in nuclear gene expression and pathway traffic ..
  8. Pefkianaki M, Schneider A, Capasso J, Wasserman B, Bardakjian T, Levin A. Ocular manifestations of PACS1 mutation. J AAPOS. 2018;22:323-325 pubmed publisher
    Heterozygous mutation in the PACS1 (phosphofurin acidic cluster sorting proteins 1) gene is a known cause of developmental delay, multiple congenital anomalies, dysmorphism, and ocular abnormalities...
  9. Leavitt S, SchOn A, Klein J, Manjappara U, Chaiken I, Freire E. Interactions of HIV-1 proteins gp120 and Nef with cellular partners define a novel allosteric paradigm. Curr Protein Pept Sci. 2004;5:1-8 pubmed
    ..A better understanding of these interactions would lead to improved strategies for inhibitor design against these viral targets. ..
  10. Hinners I, Wendler F, Fei H, Thomas L, Thomas G, Tooze S. AP-1 recruitment to VAMP4 is modulated by phosphorylation-dependent binding of PACS-1. EMBO Rep. 2003;4:1182-9 pubmed
  11. Pal S, Mishra M, Sudhakar D, Siddiqui M. In-silico designing of a potent analogue against HIV-1 Nef protein and protease by predicting its interaction network with host cell proteins. J Pharm Bioallied Sci. 2013;5:66-73 pubmed publisher
    ..The newly designed analogue (LOPI1) is showing significant in silico interaction with Nef protein and protease and can be taken forward as a potent drug lead, which may finally emerge out to be even better than the standard Lopinavir. ..
  12. Stern D, Cho M, Chikarmane R, Willaert R, Retterer K, Kendall F, et al. Association of the missense variant p.Arg203Trp in PACS1 as a cause of intellectual disability and seizures. Clin Genet. 2017;92:221-223 pubmed publisher
  13. Dirk B, Jacob R, Johnson A, Pawlak E, Cavanagh P, Van Nynatten L, et al. Viral bimolecular fluorescence complementation: a novel tool to study intracellular vesicular trafficking pathways. PLoS ONE. 2015;10:e0125619 pubmed publisher
    ..In summary, viral BiFC is a unique tool designed to analyze the interaction between Nef and host cellular proteins by mapping the sub-cellular locations of their interactions during viral infection. ..
  14. Stove V, Naessens E, Stove C, Swigut T, Plum J, Verhasselt B. Signaling but not trafficking function of HIV-1 protein Nef is essential for Nef-induced defects in human intrathymic T-cell development. Blood. 2003;102:2925-32 pubmed
    ..These results point to sites in Nef to target therapeutically for restoration of thymopoiesis in HIV infection. ..
  15. Miyake N, Ozasa S, Mabe H, Kimura S, Shiina M, Imagawa E, et al. A novel missense mutation affecting the same amino acid as the recurrent PACS1 mutation in Schuurs-Hoeijmakers syndrome. Clin Genet. 2017;: pubmed publisher
    A novel causative variant (c.608G>A, p.Arg203Gln) in PACS1.
  16. Song Q, Song J, Wang Y, Wang S, Yang Y, Meng X, et al. Association Study of Three Gene Polymorphisms Recently Identified by a Genome-Wide Association Study with Obesity-Related Phenotypes in Chinese Children. Obes Facts. 2017;10:179-190 pubmed publisher
    ..The pooled odds ratios of the A-allele of rs564343 in PACS1 for obesity and severe obesity were 1.180 (p = 0.03) and 1.312 (p = 0.004), respectively...
  17. Budhiraja S, Liu H, Couturier J, Malovannaya A, Qin J, Lewis D, et al. Mining the human complexome database identifies RBM14 as an XPO1-associated protein involved in HIV-1 Rev function. J Virol. 2015;89:3557-67 pubmed publisher
    ..This study validates the nuclear complexome database as a reference that can be mined to identify viral cofactors. ..
  18. Dikeakos J, Thomas L, Kwon G, Elferich J, Shinde U, Thomas G. An interdomain binding site on HIV-1 Nef interacts with PACS-1 and PACS-2 on endosomes to down-regulate MHC-I. Mol Biol Cell. 2012;23:2184-97 pubmed publisher
    ..Our results provide insight into the molecular basis of Nef action and suggest new strategies to combat HIV-1. ..
  19. Schuurs Hoeijmakers J, Landsverk M, Foulds N, Kukolich M, Gavrilova R, Greville Heygate S, et al. Clinical delineation of the PACS1-related syndrome--Report on 19 patients. Am J Med Genet A. 2016;170:670-5 pubmed publisher
    We report on 19 individuals with a recurrent de novo c.607C>T mutation in PACS1. This specific mutation gives rise to a recognizable intellectual disability syndrome...
  20. Thomas G, Aslan J, Thomas L, Shinde P, Shinde U, Simmen T. Caught in the act - protein adaptation and the expanding roles of the PACS proteins in tissue homeostasis and disease. J Cell Sci. 2017;130:1865-1876 pubmed publisher
    ..These discoveries suggest that investigation of the evolving PACS protein family provides a rich opportunity for insight into vertebrate cell and organ homeostasis. ..
  21. Sun M, Zhang H. Par3 and aPKC regulate BACE1 endosome-to-TGN trafficking through PACS1. Neurobiol Aging. 2017;60:129-140 pubmed publisher
    ..phosphorylation of BACE1 on Ser498, which in turn promotes the interaction between BACE1 and phosphofurin acidic cluster sorting protein 1 and facilitates the retrograde trafficking of BACE1 to the TGN...
  22. Wheeler E, Huang N, Bochukova E, Keogh J, Lindsay S, Garg S, et al. Genome-wide SNP and CNV analysis identifies common and low-frequency variants associated with severe early-onset obesity. Nat Genet. 2013;45:513-7 pubmed publisher
    ..971 severely obese children and 1,990 controls identified 4 new loci associated with severe obesity (LEPR, PRKCH, PACS1 and RMST)...
  23. Schuurs Hoeijmakers J, Oh E, Vissers L, Swinkels M, Gilissen C, Willemsen M, et al. Recurrent de novo mutations in PACS1 cause defective cranial-neural-crest migration and define a recognizable intellectual-disability syndrome. Am J Hum Genet. 2012;91:1122-7 pubmed publisher
    ..Exome sequencing in both families identified identical de novo mutations in PACS1, suggestive of causality...
  24. Scott G, Gu F, Crump C, Thomas L, Wan L, Xiang Y, et al. The phosphorylation state of an autoregulatory domain controls PACS-1-directed protein traffic. EMBO J. 2003;22:6234-44 pubmed
    ..These results suggest that coordinated signaling events regulate transport within the TGN/endosomal system through the phosphorylation state of both cargo and the sorting machinery. ..
  25. Baugh L, Garcia J, Foster J. Functional characterization of the human immunodeficiency virus type 1 Nef acidic domain. J Virol. 2008;82:9657-67 pubmed publisher
    ..Our results are consistent with an alternative model in which (62)EEEE(65) plays a stabilizing role in the formation of a ternary complex between Nef, the MHC-I cytoplasmic domain, and AP-1. ..
  26. Schmidt V, Sporbert A, Rohe M, Reimer T, Rehm A, Andersen O, et al. SorLA/LR11 regulates processing of amyloid precursor protein via interaction with adaptors GGA and PACS-1. J Biol Chem. 2007;282:32956-64 pubmed
    ..Thus, our findings identified altered routing of sorLA as a major cellular mechanism contributing to abnormal APP processing and enhanced amyloid beta-peptide formation. ..
  27. Brasacchio D, Alsop A, Noori T, Lufti M, Iyer S, Simpson K, et al. Epigenetic control of mitochondrial cell death through PACS1-mediated regulation of BAX/BAK oligomerization. Cell Death Differ. 2017;24:961-970 pubmed publisher
    ..Here we show that PCAF and ADA3 regulate the expression of PACS1, whose protein product is a key component of the machinery that sorts proteins among the trans-Golgi network and ..
  28. Burgert T, Schmidt V, Caglayan S, Lin F, Füchtbauer A, Füchtbauer E, et al. SORLA-dependent and -independent functions for PACS1 in control of amyloidogenic processes. Mol Cell Biol. 2013;33:4308-20 pubmed publisher
    ..We focused on the interaction of SORLA with phosphofurin acidic cluster sorting protein 1 (PACS1), an adaptor that shuttles proteins between the trans-Golgi network (TGN) and endosomes...