DOI QR코드

DOI QR Code

C-terminally mutated tubby protein accumulates in aggresomes

  • Kim, Sunshin ;
  • Sung, Ho Jin ;
  • Lee, Ji Won ;
  • Kim, Yun Hee ;
  • Oh, Yong-Seok ;
  • Yoon, Kyong-Ah ;
  • Heo, Kyun ;
  • Suh, Pann-Ghill
  • Received : 2016.08.12
  • Accepted : 2016.09.29
  • Published : 2017.01.31

Abstract

The tubby protein (Tub), a putative transcription factor, plays important roles in the maintenance and function of neuronal cells. A splicing defect-causing mutation in the 3'-end of the tubby gene, which is predicted to disrupt the carboxy-terminal region of the Tub protein, causes maturity-onset obesity, blindness, and deafness in mice. Although this pathological Tub mutation leads to a loss of function, the precise mechanism has not yet been investigated. Here, we found that the mutant Tub proteins were mostly localized to puncta found in the perinuclear region and that the C-terminus was important for its solubility. Immunocytochemical analysis revealed that puncta of mutant Tub co-localized with the aggresome. Moreover, whereas wild-type Tub was translocated to the nucleus by extracellular signaling, the mutant forms failed to undergo such translocation. Taken together, our results suggest that the malfunctions of the Tub mutant are caused by its misfolding and subsequent localization to aggresomes.

Keywords

Aggresome;Misfolding;Mutation;Obesity;Tubby

References

  1. Coleman D and Eicher E (1990) Fat (fat) and tubby (tub): two autosomal recessive mutations causing obesity syndromes in the mouse. J Hered 81, 424-427 https://doi.org/10.1093/oxfordjournals.jhered.a111019
  2. Kleyn PW, Fan W, Kovats SG et al (1996) Identification and characterization of the mouse obesity gene tubby: a member of a novel gene family. Cell 85, 281-290 https://doi.org/10.1016/S0092-8674(00)81104-6
  3. Noben-Trauth K, Naggert JK, North MA and Nishina PM (1996) A candidate gene for the mouse mutation tubby. Nature 380, 534-538 https://doi.org/10.1038/380534a0
  4. North MA, Naggert JK, Yan Y, Noben-Trauth K and Nishina PM (1997) Molecular characterization of TUB, TULP1, and TULP2, members of the novel tubby gene family and their possible relation to ocular diseases. Proc Natl Acad Sci U S A 94, 3128-3133 https://doi.org/10.1073/pnas.94.7.3128
  5. Carroll K, Gomez C and Shapiro L (2004) Tubby proteins: the plot thickens. Nat Rev Mol Cell Biol 5, 55-64
  6. Mukhopadhyay S and Jackson PK (2011) The tubby family proteins. Genome Biol 12, 225 https://doi.org/10.1186/gb-2011-12-6-225
  7. Hagstrom SA, North MA, Nishina PM, Berson EL and Dryja TP (1998) Recessive mutations in the gene encoding the tubby-like protein TULP1 in patients with retinitis pigmentosa. Nat Genet 18, 174-176 https://doi.org/10.1038/ng0298-174
  8. Banerjeel P, Kleyn PW, Knowles JA et al (1998) TULP1 mutation in two extended Dominican kindreds with autosomal recessive Retinitis pigmentosa. Nat Genet 18, 177-179 https://doi.org/10.1038/ng0298-177
  9. Ikeda S, Shiva N, Ikeda A et al (2000) Retinal degeneration but not obesity is observed in null mutants of the tubby-like protein 1 gene. Hum Mol Genet 9, 155-163 https://doi.org/10.1093/hmg/9.2.155
  10. Ikeda A, Ikeda S, Gridley T, Nishina PM and Naggert JK (2001) Neural tube defects and neuroepithelial cell death in Tulp3 knockout mice. Hum Mol Genet 10, 1325-1334 https://doi.org/10.1093/hmg/10.12.1325
  11. Patterson VL, Damrau C, Paudyal A et al (2009) Mouse hitchhiker mutants have spina bifida, dorso-ventral patterning defects, and polydactyly: identification of Tulp3 as a novel negative regulator of the Sonic hedgehog pathway. Hum Mol Genet 18, 1719-1739 https://doi.org/10.1093/hmg/ddp075
  12. Santagata S, Boggon TJ, Baird CL et al (2001) G-protein signaling through tubby proteins. Science 292, 2041-2050 https://doi.org/10.1126/science.1061233
  13. Prada PO, Quaresma PG, Caricilli AM et al (2013) Tub has a key role in insulin and leptin signaling and action in vivo in hypothalamic nuclei. Diabetes 62, 137-148 https://doi.org/10.2337/db11-1388
  14. Boggon TJ, Shan W-S, Santagata S, Myers SC and Shapiro L (1999) Implication of tubby proteins as transcription factors by structure-based functional analysis. Science 286, 2119-2125 https://doi.org/10.1126/science.286.5447.2119
  15. Stubdal H, Lynch CA, Moriarty A et al (2000) Targeted deletion of the tub mouse obesity gene reveals that tubby is a loss-of-function mutation. Mol Cell Biol 20, 878-882 https://doi.org/10.1128/MCB.20.3.878-882.2000
  16. Jia B, Wu Y and Zhou Y (2014) 14-3-3 and aggresome formation: implications in neurodegenerative diseases. Prion 8, 173-177 https://doi.org/10.4161/pri.28123
  17. Kopito RR (2000) Aggresomes, inclusion bodies and protein aggregation. Trends Cell Biol 10, 524-530 https://doi.org/10.1016/S0962-8924(00)01852-3
  18. Garcia-Mata R, Gao YS and Sztul E (2002) Hassles with taking out the garbage: aggravating aggresomes. Traffic 3, 388-396 https://doi.org/10.1034/j.1600-0854.2002.30602.x
  19. Garcia-Mata R, Bebok Z, Sorscher EJ and Sztul ES (1999) Characterization and Dynamics of Aggresome Formation by a Cytosolic GFP-Chimera. J Cell Biol 146, 1239-1254 https://doi.org/10.1083/jcb.146.6.1239
  20. Debure L, Vayssiere J-l, Rincheval V, Loison F, Le Drean Y and Michel D (2003) Intracellular clusterin causes juxtanuclear aggregate formation and mitochondrial alteration. J Cell Sci 116, 3109-3121 https://doi.org/10.1242/jcs.00619
  21. Kapeller R, Moriarty A, Strauss A et al (1999) Tyrosine phosphorylation of tub and its association with Src homology 2 domain-containing proteins implicate tub in intracellular signaling by insulin. J Biol Chem 274, 24980-24986 https://doi.org/10.1074/jbc.274.35.24980
  22. Heo K, Park KA, Kim YH et al (2009) Sphingosine 1-phosphate induces vascular endothelial growth factor expression in endothelial cells. BMB Rep 42, 685-690 https://doi.org/10.5483/BMBRep.2009.42.10.685

Cited by

  1. Primary cilia proteins: ciliary and extraciliary sites and functions vol.75, pp.9, 2018, https://doi.org/10.1007/s00018-017-2740-5

Acknowledgement

Supported by : National Cancer Center, National Research Foundation of Korea (NRF)