SpringerLink
Log in

BBS4 Is Essential for Nuclear Transport of Transcription Factors Mediating Neuronal ER Stress Response

  • Published:
Molecular Neurobiology Aims and scope Submit manuscript

Abstract

Bardet-Biedl syndrome (BBS) is an autosomal recessive syndrome presenting with retinal dystrophy, cognitive impairment, and obesity. BBS is characterized by elevated endoplasmic reticulum (ER) stress in the early stages of adipocyte and retinal development. BBS expression in the CNS and indications of hippocampal dysgenesis suggest neural development abnormalities. However, the role of BBS in ER stress in neuronal cells has not yet been studied. Therefore, we aimed at studying the role of BBS4 in neuronal development under normal and ER stress conditions. ER stress and unfolded protein response (UPR) were studied in BBS4-silenced (SiBBS4) SH-SY5Y cells during differentiation under normal and stress states, using molecular and biochemical markers. ER stress was demonstrated at early neural differentiation, with significantly augmented expression of UPR markers corresponding to BBS4 expression. In the undifferentiated state, BBS4 silencing resulted in significantly reduced ER-stress markers’ expression under normal and ER-stress states. Independent of ER stress, SiBBS4 cells demonstrated significant reduction in activated phospho-IRE1α. Under BBS4 silencing, both sXBP-1 and activated ATF6α p50 failed to translocate to the nucleus. Transcript levels of apoptosis markers were upregulated under BBS4 depletion and ER-stress induction, corresponding to decreased viability. BBS4 depletion in neuronal cells results in reduced sensitivity to ER stress during differentiation and under ER-stress induction, partly due to failure in translocation of ER-transcription factors (TF) sXBP-1 and ATF6α p50 to the nucleus. Hence, BBS4 is essential for nuclear transport under ER-stress response in neuronal cells during early differentiation. Our studies shed light on molecular mechanisms through which BBS4 malfunction alters neuronal ER stress response.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Subscribe and save

Springer+ Basic
EUR 32.99 /Month
  • Get 10 units per month
  • Download Article/Chapter or Ebook
  • 1 Unit = 1 Article or 1 Chapter
  • Cancel anytime
Subscribe now

Buy Now

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1
Fig. 2
Fig. 3
Fig. 4
Fig. 5
Fig. 6

Similar content being viewed by others

Abbreviations

BBS:

Bardet-Biedl syndrome

UPR:

Unfolded protein response

ER:

Endoplasmic reticulum

TM:

Tunicamycin

BiP:

Binding protein

XBP-1:

X-box binding protein 1

IRE1α:

Inositol-requiring 1α

ATF6α:

Activating transcription factor 6α

CHOP:

C/EBP homologous protein

Bax:

Pro-apoptotic Bcl-2 associated X-protein

Bcl-2:

Anti-apoptotic marker B cell lymphoma 2

PD:

Parkinson’s disease

AD:

Alzheimer’s disease

ALS:

Amyotrophic lateral sclerosis

HD:

Huntington disease

References

  1. Forsythe E, Beales PL (2013) Bardet–Biedl syndrome. Eur J Hum Genet 21:8–13. https://doi.org/10.1038/ejhg.2012.115

    Article  CAS  PubMed  Google Scholar 

  2. Álvarez-Satta M, Castro-Sánchez S, Valverde D (2017) Bardet-Biedl syndrome as a chaperonopathy: dissecting the major role of chaperonin-like BBS proteins (BBS6-BBS10-BBS12). Front Mol Biosci 4:55. https://doi.org/10.3389/fmolb.2017.00055

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  3. Anosov M, Birk R (2019) Bardet-Biedl syndrome obesity: BBS4 regulates cellular ER stress in early adipogenesis. Mol Genet Metab 126:495–503. https://doi.org/10.1016/j.ymgme.2019.03.006

    Article  CAS  PubMed  Google Scholar 

  4. Loktev AV, Zhang Q, Beck JS, Searby CC, Scheetz TE, Bazan JF, Slusarski DC, Sheffield VC et al (2008) A BBSome subunit links ciliogenesis, microtubule stability, and acetylation. Dev Cell 15:854–865. https://doi.org/10.1016/j.devcel.2008.11.001

    Article  CAS  PubMed  Google Scholar 

  5. Liu P, Lechtreck KF (2018) The Bardet–Biedl syndrome protein complex is an adapter expanding the cargo range of intraflagellar transport trains for ciliary export. Proc Natl Acad Sci 115:E934–E943. https://doi.org/10.1073/pnas.1713226115

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  6. Khan SA, Muhammad N, Khan MA, Kamal A, Rehman ZU, Khan S (2016) Genetics of human Bardet-Biedl syndrome, an updates: genetics of human Bardet-Biedl syndrome. Clin Genet 90:3–15. https://doi.org/10.1111/cge.12737

    Article  CAS  PubMed  Google Scholar 

  7. Chiang AP, Beck JS, Yen H-J, Tayeh MK, Scheetz TE, Swiderski RE, Nishimura DY, Braun TA et al (2006) Homozygosity map** with SNP arrays identifies TRIM32, an E3 ubiquitin ligase, as a Bardet-Biedl syndrome gene (BBS11). Proc Natl Acad Sci 103:6287–6292. https://doi.org/10.1073/pnas.0600158103

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  8. Leitch CC, Zaghloul NA, Davis EE, Stoetzel C, Diaz-Font A, Rix S, Alfadhel M, Lewis RA et al (2008) Hypomorphic mutations in syndromic encephalocele genes are associated with Bardet-Biedl syndrome. Nat Genet 40:443–448. https://doi.org/10.1038/ng.97

    Article  CAS  PubMed  Google Scholar 

  9. Otto EA, Hurd TW, Airik R, Chaki M, Zhou W, Stoetzel C, Patil SB, Levy S et al (2010) Candidate exome capture identifies mutation of SDCCAG8 as the cause of a retinal-renal ciliopathy. Nat Genet 42:840–850. https://doi.org/10.1038/ng.662

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  10. Heon E, Kim G, Qin S, Garrison JE, Tavares E, Vincent A, Nuangchamnong N, Scott CA et al (2016) Mutations in C8ORF37 cause Bardet Biedl syndrome (BBS21). Hum Mol Genet 25:2283–2294. https://doi.org/10.1093/hmg/ddw096

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  11. Weihbrecht K, Goar WA, Pak T et al (2017) Kee** an eye on Bardet-Biedl syndrome: a comprehensive review of the role of Bardet-Biedl syndrome genes in the eye. Med Res Arch 5. https://doi.org/10.18103/mra.v5i9.1526

  12. Fattahi Z, Rostami P, Najmabadi A, Mohseni M, Kahrizi K, Akbari MR, Kariminejad A, Najmabadi H (2014) Mutation profile of BBS genes in Iranian patients with Bardet-Biedl syndrome: genetic characterization and report of nine novel mutations in five BBS genes. J Hum Genet 59:368–375. https://doi.org/10.1038/jhg.2014.28

    Article  CAS  PubMed  Google Scholar 

  13. Muller J, Stoetzel C, Vincent MC, Leitch CC, Laurier V, Danse JM, Hellé S, Marion V et al (2010) Identification of 28 novel mutations in the Bardet-Biedl syndrome genes: the burden of private mutations in an extensively heterogeneous disease. Hum Genet 127:583–593. https://doi.org/10.1007/s00439-010-0804-9

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  14. Xu Y, Cao J, Huang S, Feng D, Zhang W, Zhu X, Yan X (2015) Characterization of tetratricopeptide repeat-containing proteins critical for cilia formation and function. PloS One 10:e0124378. https://doi.org/10.1371/journal.pone.0124378

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  15. Domire JS, Green JA, Lee KG, Johnson AD, Askwith CC, Mykytyn K (2011) Dopamine receptor 1 localizes to neuronal cilia in a dynamic process that requires the Bardet-Biedl syndrome proteins. Cell Mol Life Sci 68:2951–2960. https://doi.org/10.1007/s00018-010-0603-4

    Article  CAS  PubMed  Google Scholar 

  16. Leitch CC, Zaghloul NA (2014) BBS4 is necessary for ciliary localization of TrkB receptor and activation by BDNF. PLoS ONE 9:e98687. https://doi.org/10.1371/journal.pone.0098687

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  17. Prieto-Echagüe V, Lodh S, Colman L, Bobba N, Santos L, Katsanis N, Escande C, Zaghloul NA et al (2017) BBS4 regulates the expression and secretion of FSTL1, a protein that participates in ciliogenesis and the differentiation of 3T3-L1. Sci Rep 7:9765. https://doi.org/10.1038/s41598-017-10330-0

    Article  PubMed  PubMed Central  Google Scholar 

  18. Han Y-G, Alvarez-Buylla A (2010) Role of primary cilia in brain development and cancer. Curr Opin Neurobiol 20:58–67. https://doi.org/10.1016/j.conb.2009.12.002

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  19. Eichers ER, Abd-El-Barr MM, Paylor R et al (2006) Phenotypic characterization of Bbs4 null mice reveals age-dependent penetrance and variable expressivity. Hum Genet 120:211–226. https://doi.org/10.1007/s00439-006-0197-y

    Article  CAS  PubMed  Google Scholar 

  20. Carter CS, Vogel TW, Zhang Q, Seo S, Swiderski RE, Moninger TO, Cassell MD, Thedens DR et al (2012) Abnormal development of NG2+PDGFR-α+ neural progenitor cells leads to neonatal hydrocephalus in a ciliopathy mouse model. Nat Med 18:1797–1804. https://doi.org/10.1038/nm.2996

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  21. Lechtreck K-F, Delmotte P, Robinson ML, Sanderson MJ, Witman GB (2008) Mutations in Hydin impair ciliary motility in mice. J Cell Biol 180:633–643. https://doi.org/10.1083/jcb.200710162

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  22. Chamling X, Seo S, Bugge K, Searby C, Guo DF, Drack AV, Rahmouni K, Sheffield VC (2013) Ectopic expression of human BBS4 can rescue Bardet-Biedl syndrome phenotypes in Bbs4 null mice. PLoS ONE 8:e59101. https://doi.org/10.1371/journal.pone.0059101

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  23. Ross AJ, May-Simera H, Eichers ER, Kai M, Hill J, Jagger DJ, Leitch CC, Chapple JP et al (2005) Disruption of Bardet-Biedl syndrome ciliary proteins perturbs planar cell polarity in vertebrates. Nat Genet 37:1135–1140. https://doi.org/10.1038/ng1644

    Article  CAS  PubMed  Google Scholar 

  24. Aksanov O, Green P, Birk RZ (2014) BBS4 directly affects proliferation and differentiation of adipocytes. Cell Mol Life Sci 71:3381–3392. https://doi.org/10.1007/s00018-014-1571-x

    Article  CAS  PubMed  Google Scholar 

  25. Ariyasu D, Yoshida H, Hasegawa Y (2017) Endoplasmic reticulum (ER) stress and endocrine disorders. Int J Mol Sci 18. https://doi.org/10.3390/ijms18020382

  26. Mercado G, Castillo V, Soto P, Sidhu A (2016) ER stress and Parkinson’s disease: pathological inputs that converge into the secretory pathway. Brain Res 1648:626–632. https://doi.org/10.1016/j.brainres.2016.04.042

    Article  CAS  PubMed  Google Scholar 

  27. Gerakis Y, Hetz C (2018) Emerging roles of ER stress in the etiology and pathogenesis of Alzheimer’s disease. FEBS J 285:995–1011. https://doi.org/10.1111/febs.14332

    Article  CAS  PubMed  Google Scholar 

  28. Montibeller L, de Belleroche J (2018) Amyotrophic lateral sclerosis (ALS) and Alzheimer’s disease (AD) are characterised by differential activation of ER stress pathways: focus on UPR target genes. Cell Stress Chaperones 23:897–912. https://doi.org/10.1007/s12192-018-0897-y

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  29. Liu Y, Connor J (2015) From adaption to death: endoplasmic reticulum stress as a novel target of selective neurodegeneration? Neural Regen Res 10:1397. https://doi.org/10.4103/1673-5374.165227

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  30. Fischer JW, Leung AKL (2017) CircRNAs: a regulator of cellular stress. Crit Rev Biochem Mol Biol 52:220–233. https://doi.org/10.1080/10409238.2016.1276882

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  31. Mockel A, Obringer C, Hakvoort TBM, Seeliger M, Lamers WH, Stoetzel C, Dollfus H, Marion V (2012) Pharmacological modulation of the retinal unfolded protein response in Bardet-Biedl syndrome reduces apoptosis and preserves light detection ability. J Biol Chem 287:37483–37494. https://doi.org/10.1074/jbc.M112.386821

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  32. Schönthal AH (2012) Endoplasmic reticulum stress: its role in disease and novel prospects for therapy. Scientifica 2012:1–26. https://doi.org/10.6064/2012/857516

    Article  CAS  Google Scholar 

  33. Pagliassotti MJ, Kim PY, Estrada AL, Stewart CM, Gentile CL (2016) Endoplasmic reticulum stress in obesity and obesity-related disorders: an expanded view. Metabolism 65:1238–1246. https://doi.org/10.1016/j.metabol.2016.05.002

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  34. Stagg SM, LaPointe P, Balch WE (2007) Structural design of cage and coat scaffolds that direct membrane traffic. Curr Opin Struct Biol 17:221–228. https://doi.org/10.1016/j.sbi.2007.03.010

    Article  CAS  PubMed  Google Scholar 

  35. ** H, White SR, Shida T, Schulz S, Aguiar M, Gygi SP, Bazan JF, Nachury MV (2010) The conserved Bardet-Biedl syndrome proteins assemble a coat that traffics membrane proteins to cilia. Cell 141:1208–1219. https://doi.org/10.1016/j.cell.2010.05.015

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  36. Walter F, O’Brien A, Concannon CG et al (2018) ER stress signaling has an activating transcription factor 6α (ATF6)-dependent “off-switch”. J Biol Chem 293:18270–18284. https://doi.org/10.1074/jbc.RA118.002121

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  37. Yoshida H, Matsui T, Yamamoto A, Okada T, Mori K (2001) XBP1 mRNA is induced by ATF6 and spliced by IRE1 in response to ER stress to produce a highly active transcription factor. Cell 107:881–891. https://doi.org/10.1016/S0092-8674(01)00611-0

    Article  CAS  PubMed  Google Scholar 

  38. Puthalakath H, O’Reilly LA, Gunn P et al (2007) ER stress triggers apoptosis by activating BH3-only protein Bim. Cell 129:1337–1349. https://doi.org/10.1016/j.cell.2007.04.027

    Article  CAS  PubMed  Google Scholar 

  39. Sun X, Li W, Deng Y, Dong B, Sun Y, Xue Y, Wang Y (2018) Hepatic conditional knockout of ATF6 exacerbates liver metabolic damage by repressing autophage through MTOR pathway. Biochem Biophys Res Commun 505:45–50. https://doi.org/10.1016/j.bbrc.2018.09.047

    Article  CAS  PubMed  Google Scholar 

  40. Vadde R, Radhakrishnan S, Reddivari L, Vanamala JKP (2015) Triphala extract suppresses proliferation and induces apoptosis in human colon cancer stem cells via suppressing c-Myc/cyclin D1 and elevation of Bax/Bcl-2 ratio. BioMed Res Int 2015:1–12. https://doi.org/10.1155/2015/649263

    Article  CAS  Google Scholar 

  41. Yi J, Yang X, Zheng L, Yang G, Sun L, Bao Y, Wu Y, Huang Y et al (2015) Photoactivation of hypericin decreases the viability of RINm5F insulinoma cells through reduction in JNK/ERK phosphorylation and elevation of caspase-9/caspase-3 cleavage and Bax-to-Bcl-2 ratio. Biosci Rep 35:e00195. https://doi.org/10.1042/BSR20150028

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  42. Bu L-J, Yu H-Q, Fan L-L, Li XQ, Wang F, Liu JT, Zhong F, Zhang CJ et al (2017) Melatonin, a novel selective ATF-6 inhibitor, induces human hepatoma cell apoptosis through COX-2 downregulation. World J Gastroenterol 23:986. https://doi.org/10.3748/wjg.v23.i6.986

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  43. Dadey DYA, Kapoor V, Khudanyan A et al (2016) The ATF6 pathway of the ER stress response contributes to enhanced viability in glioblastoma. Oncotarget 7. https://doi.org/10.18632/oncotarget.6712

  44. Hetz C, Saxena S (2017) ER stress and the unfolded protein response in neurodegeneration. Nat Rev Neurol 13:477–491. https://doi.org/10.1038/nrneurol.2017.99

    Article  CAS  PubMed  Google Scholar 

  45. **ang C, Wang Y, Zhang H, Han F (2017) The role of endoplasmic reticulum stress in neurodegenerative disease. Apoptosis 22:1–26. https://doi.org/10.1007/s10495-016-1296-4

    Article  CAS  PubMed  Google Scholar 

  46. Sarvani C, Sireesh D, Ramkumar KM (2017) Unraveling the role of ER stress inhibitors in the context of metabolic diseases. Pharmacol Res 119:412–421. https://doi.org/10.1016/j.phrs.2017.02.018

    Article  CAS  PubMed  Google Scholar 

Download references

Author information

Authors and Affiliations

  1. Department of Nutrition, Faculty of Health Sciences, Ariel University, Ariel, Israel

    Avital Horwitz & Ruth Birk

Authors
  1. Avital Horwitz
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Ruth Birk
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Ruth Birk.

Ethics declarations

Conflict of Interest

The authors declare that the results of this work are part of a filed patent.

Additional information

Publisher’s Note

Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Horwitz, A., Birk, R. BBS4 Is Essential for Nuclear Transport of Transcription Factors Mediating Neuronal ER Stress Response. Mol Neurobiol 58, 78–91 (2021). https://doi.org/10.1007/s12035-020-02104-z

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s12035-020-02104-z

Keywords

Search

Navigation