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Investigating the Impact of Birt–Hogg–Dubé Syndrome Associated Folliculin (FLCN) and Retinitis Pigmentosa 2 (RP2) Loss on Cilia Function and Morphology

Year 2024, Volume: 45 Issue: 2, 235 - 239, 30.06.2024

Oktay İsmail Kaplan

https://doi.org/10.17776/csj.1398415

Abstract

Folliculin (FLCN), a GTPase-activating protein (GAP), has been linked to Birt–Hogg–Dubé syndrome, the mTORC1 signaling pathway and cilia. Disruptions in cilia structure and function lead to a group of diseases known as ciliopathies. Birt-Hogg-Dubé syndrome is one of 35 different ciliopathy diseases and there are more than 250 genes that cause ciliopathy diseases. FLCN interacts with kinesin-2 along cilia. The specific role of FLCN in regulating Kinesin-IFT trafficking has, however, remained unclear. In the current study, we investigated the effects of flcn-1 loss (the human ortholog of FLCN) on kinesin and IFT trafficking in C. elegans. The loss of flcn-1 alone did not result in any apparent alterations to kinesin or IFT trafficking within the cilia. However, when we combined the deletion of flcn-1 with the deletion of Retinitis Pigmentosa 2 (RP2), another GAP protein, the ciliary entry of a non-ciliary membrane protein TRAM-1 (Translocation Associated Membrane Protein 1) occured. Additionally, although cilia length was unaltered, our analysis of double mutants revealed the extra branch in wing AWB cilia morphology but not the single rod-like PHA/PHB cilia. In summary, our study reveals the previously unknown functions of FLCN in ciliary gating and cilia morphology in C. elegans

Keywords

Folliculin Cilia Retinitis pigmentosa 2 Ciliary gate

References

  • [1] Satir P, Christensen ST., Overview of Structure and Function of Mammalian Cilia, Annu Rev Physiol., 69(1) (2007) 377-400.
  • [2] Mitchison HM, Valente EM. Motile and non-motile cilia in human pathology: from function to phenotypes: Motile and non-motile ciliopathies, J. Pathol., 241(2) (2017) 294-309.
  • [3] Shah AS, Ben-Shahar Y, Moninger TO, Kline JN, Welsh MJ., Motile Cilia of Human Airway Epithelia Are Chemosensory, Science, 325(5944) (2009) 1131-1134.
  • [4] Turan MG, Orhan ME, Cevik S, Kaplan OI., CiliaMiner: an integrated database for ciliopathy genes and ciliopathies, Database., (2023) baad047.
  • [5] Kozminski KG, Johnson KA, Forscher P, Rosenbaum JL., A motility in the eukaryotic flagellum unrelated to flagellar beating, Proc Natl Acad Sci., 90(12) (1993) 5519-5523.
  • [6] Kozminski KG, Beech PL, Rosenbaum JL., The Chlamydomonas kinesin-like protein FLA10 is involved in motility associated with the flagellar membrane, J Cell Biol., 131(6) (1995) 1517-1527.
  • [7] Rosenbaum JL, Witman GB., Intraflagellar transport, Nat Rev Mol Cell Biol., 3(11) (2002) 813-825.
  • [8] Blacque OE, Cevik S, Kaplan OI., Intraflagellar transport: from molecular characterisation to mechanism, Front Biosci., 13(13) (2008) 2633.
  • [9] Zhong M, Zhao X, Li J, Yuan W, Yan G, Tong M, Guo S, Zhu Y, Jiang Y, Liu Y, Jiang Y, Tumor Suppressor Folliculin Regulates mTORC1 through Primary Cilia, J Biol Chem., 291(22) (2016) 11689-11697.
  • [10] Possik E, Jalali Z, Nouët Y, Yan M, Gingras MC, Schmeisser K, Panaite L, Dupuy F, Kharitidi D, Chotard L, Jones RG, Hall DH, Pause A., Folliculin Regulates Ampk-Dependent Autophagy and Metabolic Stress Survival, PLoS Genet., 10(4) (2014) e1004273.
  • [11] Baba M, Toyama H, Sun L, Takubo K, Suh HC, Hasumi H, Nakamura-Ishizu A, Hasumi Y, Klarmann KD, Nakagata N, Schmidt LS, Linehan WM, Suda T, Keller JR. Loss of Folliculin Disrupts Hematopoietic Stem Cell Quiescence and Homeostasis Resulting in Bone Marrow Failure, Stem Cells., 34(4) (2016) 1068-1082.
  • [12] Dunlop EA, Seifan S, Claessens T, Behrends C, Kamps MA, Rozycka E, Kemp AJ, Nookala RK, Blenis J, Coull BJ, Murray JT, van Steensel MA, Wilkinson S, Tee AR., FLCN, a novel autophagy component, interacts with GABARAP and is regulated by ULK1 phosphorylation, Autophagy., 10(10) (2014) 1749-1760.
  • [13] Luijten MN, Basten SG, Claessens T, Vernooij M, Scott CL, Janssen R, Easton JA, Kamps MA, Vreeburg M, Broers JL, van Geel M, Menko FH, Harbottle RP, Nookala RK, Tee AR, Land SC, Giles RH, Coull BJ, van Steensel MA., Birt–Hogg–Dubé syndrome is a novel ciliopathy, Hum Mol Genet., 22(21) (2013) 4383-4397.
  • [14] Zhang Y, Liu Y, Dai Y, Ren Y, Bao G, Ai B, Jiang Y., Ciliary localization of folliculin mediated via a kinesin‐2‐binding motif is required for its functions in mTOR regulation and tumor suppression, FEBS Lett., 595(1) (2021) 123-132.
  • [15] Hasumi Y, Baba M, Hasumi H, Huang Y, Lang M, Reindorf R, Oh HB, Sciarretta S, Nagashima K, Haines DC, Schneider MD, Adelstein RS, Schmidt LS, Sadoshima J, Marston Linehan W., Folliculin (Flcn) inactivation leads to murine cardiac hypertrophy through mTORC1 deregulation, Hum Mol Genet., 23(21) (2014) 5706-5719.
  • [16] Cevik S, Peng X, Beyer T, Pir MS, Yenisert F, Woerz F, Hoffmann F, Altunkaynak B, Pir B, Boldt K, Karaman A, Cakiroglu M, Oner SS, Cao Y, Ueffing M, Kaplan OI., WDR31 displays functional redundancy with GTPase-activating proteins (GAPs) ELMOD and RP2 in regulating IFT complex and recruiting the BBSome to cilium, Life Sci Alliance., 6(8) (2023) e202201844.
  • [17] Williams CL, Li C, Kida K, Inglis PN, Mohan S, Semenec L, Bialas NJ, Stupay RM, Chen N, Blacque OE, Yoder BK, Leroux MR., MKS and NPHP modules cooperate to establish basal body/transition zone membrane associations and ciliary gate function during ciliogenesis, J Cell Biol., 192(6) (2011) 1023-1041.

Year 2024, Volume: 45 Issue: 2, 235 - 239, 30.06.2024

Oktay İsmail Kaplan

https://doi.org/10.17776/csj.1398415

Abstract

Ethical Statement

Bu makalede herhangi bir hasta örneği kullanılmamış ya da fare çalışması yapılmamıştır.

Supporting Institution

TUSEB

Thanks

Sebiha Çevik ve Ali Sina Arslan'a teknik sdestekleri için teşekkür ederim.

References

  • [1] Satir P, Christensen ST., Overview of Structure and Function of Mammalian Cilia, Annu Rev Physiol., 69(1) (2007) 377-400.
  • [2] Mitchison HM, Valente EM. Motile and non-motile cilia in human pathology: from function to phenotypes: Motile and non-motile ciliopathies, J. Pathol., 241(2) (2017) 294-309.
  • [3] Shah AS, Ben-Shahar Y, Moninger TO, Kline JN, Welsh MJ., Motile Cilia of Human Airway Epithelia Are Chemosensory, Science, 325(5944) (2009) 1131-1134.
  • [4] Turan MG, Orhan ME, Cevik S, Kaplan OI., CiliaMiner: an integrated database for ciliopathy genes and ciliopathies, Database., (2023) baad047.
  • [5] Kozminski KG, Johnson KA, Forscher P, Rosenbaum JL., A motility in the eukaryotic flagellum unrelated to flagellar beating, Proc Natl Acad Sci., 90(12) (1993) 5519-5523.
  • [6] Kozminski KG, Beech PL, Rosenbaum JL., The Chlamydomonas kinesin-like protein FLA10 is involved in motility associated with the flagellar membrane, J Cell Biol., 131(6) (1995) 1517-1527.
  • [7] Rosenbaum JL, Witman GB., Intraflagellar transport, Nat Rev Mol Cell Biol., 3(11) (2002) 813-825.
  • [8] Blacque OE, Cevik S, Kaplan OI., Intraflagellar transport: from molecular characterisation to mechanism, Front Biosci., 13(13) (2008) 2633.
  • [9] Zhong M, Zhao X, Li J, Yuan W, Yan G, Tong M, Guo S, Zhu Y, Jiang Y, Liu Y, Jiang Y, Tumor Suppressor Folliculin Regulates mTORC1 through Primary Cilia, J Biol Chem., 291(22) (2016) 11689-11697.
  • [10] Possik E, Jalali Z, Nouët Y, Yan M, Gingras MC, Schmeisser K, Panaite L, Dupuy F, Kharitidi D, Chotard L, Jones RG, Hall DH, Pause A., Folliculin Regulates Ampk-Dependent Autophagy and Metabolic Stress Survival, PLoS Genet., 10(4) (2014) e1004273.
  • [11] Baba M, Toyama H, Sun L, Takubo K, Suh HC, Hasumi H, Nakamura-Ishizu A, Hasumi Y, Klarmann KD, Nakagata N, Schmidt LS, Linehan WM, Suda T, Keller JR. Loss of Folliculin Disrupts Hematopoietic Stem Cell Quiescence and Homeostasis Resulting in Bone Marrow Failure, Stem Cells., 34(4) (2016) 1068-1082.
  • [12] Dunlop EA, Seifan S, Claessens T, Behrends C, Kamps MA, Rozycka E, Kemp AJ, Nookala RK, Blenis J, Coull BJ, Murray JT, van Steensel MA, Wilkinson S, Tee AR., FLCN, a novel autophagy component, interacts with GABARAP and is regulated by ULK1 phosphorylation, Autophagy., 10(10) (2014) 1749-1760.
  • [13] Luijten MN, Basten SG, Claessens T, Vernooij M, Scott CL, Janssen R, Easton JA, Kamps MA, Vreeburg M, Broers JL, van Geel M, Menko FH, Harbottle RP, Nookala RK, Tee AR, Land SC, Giles RH, Coull BJ, van Steensel MA., Birt–Hogg–Dubé syndrome is a novel ciliopathy, Hum Mol Genet., 22(21) (2013) 4383-4397.
  • [14] Zhang Y, Liu Y, Dai Y, Ren Y, Bao G, Ai B, Jiang Y., Ciliary localization of folliculin mediated via a kinesin‐2‐binding motif is required for its functions in mTOR regulation and tumor suppression, FEBS Lett., 595(1) (2021) 123-132.
  • [15] Hasumi Y, Baba M, Hasumi H, Huang Y, Lang M, Reindorf R, Oh HB, Sciarretta S, Nagashima K, Haines DC, Schneider MD, Adelstein RS, Schmidt LS, Sadoshima J, Marston Linehan W., Folliculin (Flcn) inactivation leads to murine cardiac hypertrophy through mTORC1 deregulation, Hum Mol Genet., 23(21) (2014) 5706-5719.
  • [16] Cevik S, Peng X, Beyer T, Pir MS, Yenisert F, Woerz F, Hoffmann F, Altunkaynak B, Pir B, Boldt K, Karaman A, Cakiroglu M, Oner SS, Cao Y, Ueffing M, Kaplan OI., WDR31 displays functional redundancy with GTPase-activating proteins (GAPs) ELMOD and RP2 in regulating IFT complex and recruiting the BBSome to cilium, Life Sci Alliance., 6(8) (2023) e202201844.
  • [17] Williams CL, Li C, Kida K, Inglis PN, Mohan S, Semenec L, Bialas NJ, Stupay RM, Chen N, Blacque OE, Yoder BK, Leroux MR., MKS and NPHP modules cooperate to establish basal body/transition zone membrane associations and ciliary gate function during ciliogenesis, J Cell Biol., 192(6) (2011) 1023-1041.
There are 17 citations in total.

Details

Primary Language English
Subjects Biochemistry and Cell Biology (Other)
Journal Section Natural Sciences
Authors

Oktay İsmail Kaplan 0000-0002-8733-0920

Publication Date June 30, 2024
Submission Date November 30, 2023
Acceptance Date June 13, 2024
Published in Issue Year 2024Volume: 45 Issue: 2

Cite

APA Kaplan, O. İ. (2024). Investigating the Impact of Birt–Hogg–Dubé Syndrome Associated Folliculin (FLCN) and Retinitis Pigmentosa 2 (RP2) Loss on Cilia Function and Morphology. Cumhuriyet Science Journal, 45(2), 235-239. https://doi.org/10.17776/csj.1398415
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