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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

Yıl 2024, Cilt: 45 Sayı: 2, 235 - 239, 30.06.2024

Oktay İsmail Kaplan

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

Öz

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

Anahtar Kelimeler

Folliculin Cilia Retinitis pigmentosa 2 Ciliary gate

Kaynakça

  • [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.

Yıl 2024, Cilt: 45 Sayı: 2, 235 - 239, 30.06.2024

Oktay İsmail Kaplan

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

Öz

Etik Beyan

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

Destekleyen Kurum

TUSEB

Teşekkür

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

Kaynakça

  • [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.
Toplam 17 adet kaynakça vardır.

Ayrıntılar

Birincil Dil İngilizce
Konular Biyokimya ve Hücre Biyolojisi (Diğer)
Bölüm Natural Sciences
Yazarlar

Oktay İsmail Kaplan 0000-0002-8733-0920

Yayımlanma Tarihi 30 Haziran 2024
Gönderilme Tarihi 30 Kasım 2023
Kabul Tarihi 13 Haziran 2024
Yayımlandığı Sayı Yıl 2024Cilt: 45 Sayı: 2

Kaynak Göster

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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