The unfolded protein response regulates ER exit sites via SNRPB-dependent RNA splicing and contributes to bone development.
COPII
Endoplasmic Reticulum
Proteostasis
Sec16A
Splicing
Journal
The EMBO journal
ISSN: 1460-2075
Titre abrégé: EMBO J
Pays: England
ID NLM: 8208664
Informations de publication
Date de publication:
19 Aug 2024
19 Aug 2024
Historique:
received:
28
09
2023
accepted:
24
07
2024
revised:
08
07
2024
medline:
20
8
2024
pubmed:
20
8
2024
entrez:
19
8
2024
Statut:
aheadofprint
Résumé
Splicing and endoplasmic reticulum (ER)-proteostasis are two key processes that ultimately regulate the functional proteins that are produced by a cell. However, the extent to which these processes interact remains poorly understood. Here, we identify SNRPB and other components of the Sm-ring, as targets of the unfolded protein response and novel regulators of export from the ER. Mechanistically, The Sm-ring regulates the splicing of components of the ER export machinery, including Sec16A, a component of ER exit sites. Loss of function of SNRPB is causally linked to cerebro-costo-mandibular syndrome (CCMS), a genetic disease characterized by bone defects. We show that heterozygous deletion of SNRPB in mice resulted in bone defects reminiscent of CCMS and that knockdown of SNRPB delays the trafficking of type-I collagen. Silencing SNRPB inhibited osteogenesis in vitro, which could be rescued by overexpression of Sec16A. This rescue indicates that the role of SNRPB in osteogenesis is linked to its effects on ER-export. Finally, we show that SNRPB is a target for the unfolded protein response, which supports a mechanistic link between the spliceosome and ER-proteostasis. Our work highlights components of the Sm-ring as a novel node in the proteostasis network, shedding light on CCMS pathophysiology.
Identifiants
pubmed: 39160274
doi: 10.1038/s44318-024-00208-z
pii: 10.1038/s44318-024-00208-z
doi:
Types de publication
Journal Article
Langues
eng
Sous-ensembles de citation
IM
Subventions
Organisme : Austrian Science Fund (FWF)
ID : P 36600
Organisme : Austrian Science Fund (FWF)
ID : P 35832
Organisme : Austrian Science Fund (FWF)
ID : FG2000
Organisme : Austrian Science Fund (FWF)
ID : ESP634
Organisme : Norges Forskningsråd (Forskningsrådet)
ID : 302452
Organisme : Norges Forskningsråd (Forskningsrådet)
ID : 262652
Organisme : Wellcome Trust
ID : 208015
Pays : United Kingdom
Organisme : EC | Horizon Europe | Excellent Science | HORIZON EUROPE Marie Sklodowska-Curie Actions (MSCA)
ID : 860035
Organisme : EC | Horizon Europe | Excellent Science | HORIZON EUROPE Marie Sklodowska-Curie Actions (MSCA)
ID : 859962
Informations de copyright
© 2024. The Author(s).
Références
Alam SS, Kumar S, Beauchamp MC, Bareke E, Boucher A, Nzirorera N, Dong Y, Padilla R, Zhang SJ, Majewski J et al (2022) Snrpb is required in murine neural crest cells for proper splicing and craniofacial morphogenesis. Dis Model Mech 15:dmm049544
pubmed: 35593225
pmcid: 9235875
doi: 10.1242/dmm.049544
Bacrot S, Doyard M, Huber C, Alibeu O, Feldhahn N, Lehalle D, Lacombe D, Marlin S, Nitschke P, Petit F et al (2015) Mutations in SNRPB, encoding components of the core splicing machinery, cause cerebro-costo-mandibular syndrome. Hum Mutat 36:187–190
pubmed: 25504470
doi: 10.1002/humu.22729
Bakunts A, Orsi A, Vitale M, Cattaneo A, Lari F, Tadè L, Sitia R, Raimondi A, Bachi A, van Anken E (2017) Ratiometric sensing of BiP-client versus BiP levels by the unfolded protein response determines its signaling amplitude. eLife 6:e27518
pubmed: 29251598
pmcid: 5792092
doi: 10.7554/eLife.27518
Ben-Tekaya H, Miura K, Pepperkok R, Hauri HP (2005) Live imaging of bidirectional traffic from the ERGIC. J Cell Sci 118:357–367
pubmed: 15632110
doi: 10.1242/jcs.01615
Bergmann TJ, Fregno I, Fumagalli F, Rinaldi A, Bertoni F, Boersema PJ, Picotti P, Molinari M (2018) Chemical stresses fail to mimic the unfolded protein response resulting from luminal load with unfolded polypeptides. J Biol Chem 293:5600–5612
pubmed: 29453283
pmcid: 5900776
doi: 10.1074/jbc.RA117.001484
Boncompain G, Divoux S, Gareil N, de Forges H, Lescure A, Latreche L, Mercanti V, Jollivet F, Raposo G, Perez F (2012) Synchronization of secretory protein traffic in populations of cells. Nat Methods 9:493–498
pubmed: 22406856
doi: 10.1038/nmeth.1928
Boyadjiev SA, Fromme JC, Ben J, Chong SS, Nauta C, Hur DJ, Zhang G, Hamamoto S, Schekman R, Ravazzola M et al (2006) Cranio-lenticulo-sutural dysplasia is caused by a SEC23A mutation leading to abnormal endoplasmic-reticulum-to-Golgi trafficking. Nat Genet 38:1192–1197
pubmed: 16980979
doi: 10.1038/ng1876
Cui Y, Parashar S, Zahoor M, Needham PG, Mari M, Zhu M, Chen S, Ho HC, Reggiori F, Farhan H et al (2019) A COPII subunit acts with an autophagy receptor to target endoplasmic reticulum for degradation. Science 365:53–60
pubmed: 31273116
pmcid: 7062386
doi: 10.1126/science.aau9263
Dobin A, Davis CA, Schlesinger F, Drenkow J, Zaleski C, Jha S, Batut P, Chaisson M, Gingeras TR (2013) STAR: ultrafast universal RNA-seq aligner. Bioinformatics 29:15–21
pubmed: 23104886
doi: 10.1093/bioinformatics/bts635
El-Gazzar A, Voraberger B, Rauch F, Mairhofer M, Schmidt K, Guillemyn B, Mitulović G, Reiterer V, Haun M, Mayr MM et al (2023) Bi-allelic mutation in SEC16B alters collagen trafficking and increases ER stress. EMBO Mol Med 15:e16834
pubmed: 36916446
pmcid: 10086588
doi: 10.15252/emmm.202216834
Enninga J, Levay A, Fontoura BM (2003) Sec13 shuttles between the nucleus and the cytoplasm and stably interacts with Nup96 at the nuclear pore complex. Mol Cell Biol 23:7271–7284
pubmed: 14517296
pmcid: 230331
doi: 10.1128/MCB.23.20.7271-7284.2003
Farhan H, Kundu M, Ferro-Novick S (2017) The link between autophagy and secretion: a story of multitasking proteins. Mol Biol Cell 28:1161–1164
pubmed: 28468940
pmcid: 5415012
doi: 10.1091/mbc.e16-11-0762
Farhan H, Weiss M, Tani K, Kaufman RJ, Hauri HP (2008) Adaptation of endoplasmic reticulum exit sites to acute and chronic increases in cargo load. EMBO J 27:2043–2054
pubmed: 18650939
pmcid: 2516884
doi: 10.1038/emboj.2008.136
Farhan H, Wendeler MW, Mitrovic S, Fava E, Silberberg Y, Sharan R, Zerial M, Hauri HP (2010) MAPK signaling to the early secretory pathway revealed by kinase/phosphatase functional screening. J Cell Biol 189:997–1011
pubmed: 20548102
pmcid: 2886346
doi: 10.1083/jcb.200912082
Garbes L, Kim K, Rieß A, Hoyer-Kuhn H, Beleggia F, Bevot A, Kim MJ, Huh YH, Kweon HS, Savarirayan R et al (2015) Mutations in SEC24D, encoding a component of the COPII machinery, cause a syndromic form of osteogenesis imperfecta. Am J Hum Genet 96:432–439
pubmed: 25683121
pmcid: 4375534
doi: 10.1016/j.ajhg.2015.01.002
Guo F, Han X, Wu Z, Cheng Z, Hu Q, Zhao Y, Wang Y, Liu C (2016) ATF6a, a Runx2-activable transcription factor, is a new regulator of chondrocyte hypertrophy. J Cell Sci 129:717–728
pubmed: 26527399
Hetz C, Saxena S (2017) ER stress and the unfolded protein response in neurodegeneration. Nat Rev Neurol 13:477–491
pubmed: 28731040
doi: 10.1038/nrneurol.2017.99
Horiuchi K, Tohmonda T, Morioka H (2016) The unfolded protein response in skeletal development and homeostasis. Cell Mol Life Sci 73:2851–2869
pubmed: 27002737
pmcid: 11108572
doi: 10.1007/s00018-016-2178-1
Hou W, Gupta S, Beauchamp MC, Yuan L, Jerome-Majewska LA (2017) Non-alcoholic fatty liver disease in mice with heterozygous mutation in TMED2. PLoS ONE 12:e0182995
pubmed: 28797121
pmcid: 5552249
doi: 10.1371/journal.pone.0182995
Huang Y, Carmichael GG (1996) Role of polyadenylation in nucleocytoplasmic transport of mRNA. Mol Cell Biol 16:1534–1542
pubmed: 8657127
pmcid: 231138
doi: 10.1128/MCB.16.4.1534
Klaips CL, Jayaraj GG, Hartl FU (2018) Pathways of cellular proteostasis in aging and disease. J Cell Biol 217:51–63
pubmed: 29127110
pmcid: 5748993
doi: 10.1083/jcb.201709072
Kurokawa K, Nakano A (2019) The ER exit sites are specialized ER zones for the transport of cargo proteins from the ER to the Golgi apparatus. J Biochem 165:109–114
pubmed: 30304445
doi: 10.1093/jb/mvy080
Leroy JG, Devos EA, Vanden Bulcke LJ, Robbe NS (1981) Cerebro-costo-mandibular syndrome with autosomal dominant inheritance. J Pediatr 99:441–443
pubmed: 7264806
doi: 10.1016/S0022-3476(81)80343-5
Lewis AE, Vasudevan HN, O’Neill AK, Soriano P, Bush JO (2013) The widely used Wnt1-Cre transgene causes developmental phenotypes by ectopic activation of Wnt signaling. Dev Biol 379:229–234
pubmed: 23648512
pmcid: 3804302
doi: 10.1016/j.ydbio.2013.04.026
Lim WA, Lee CM, Tang C (2013) Design principles of regulatory networks: searching for the molecular algorithms of the cell. Mol Cell 49:202–212
pubmed: 23352241
pmcid: 3664230
doi: 10.1016/j.molcel.2012.12.020
Love MI, Huber W, Anders S (2014) Moderated estimation of fold change and dispersion for RNA-seq data with DESeq2. Genome Biol 15:550
pubmed: 25516281
pmcid: 4302049
doi: 10.1186/s13059-014-0550-8
Lynch DC, Revil T, Schwartzentruber J, Bhoj EJ, Innes AM, Lamont RE, Lemire EG, Chodirker BN, Taylor JP, Zackai EH et al (2014) Disrupted auto-regulation of the spliceosomal gene SNRPB causes cerebro-costo-mandibular syndrome. Nat Commun 5:4483
pubmed: 25047197
doi: 10.1038/ncomms5483
Maiuolo J, Bulotta S, Verderio C, Benfante R, Borgese N (2011) Selective activation of the transcription factor ATF6 mediates endoplasmic reticulum proliferation triggered by a membrane protein. Proc Natl Acad Sci USA 108:7832–7837
pubmed: 21521793
pmcid: 3093499
doi: 10.1073/pnas.1101379108
McNicholl B, Egan-Mitchell B, Murray JP, Doyle JF, Kennedy JD, Crome L (1970) Cerebro-costo-mandibular syndrome. A new familial developmental disorder. Arch Dis Child 45:421–424
pubmed: 5427859
pmcid: 1647602
doi: 10.1136/adc.45.241.421
Oka OBV, Pierre AS, Pringle MA, Tungkum W, Cao Z, Fleming B, Bulleid NJ (2022) Activation of the UPR sensor ATF6α is regulated by its redox-dependent dimerization and ER retention by ERp18. Proc Natl Acad Sci USA 119:e2122657119
pubmed: 35286189
pmcid: 8944254
doi: 10.1073/pnas.2122657119
Patro R, Duggal G, Love MI, Irizarry RA, Kingsford C (2017) Salmon provides fast and bias-aware quantification of transcript expression. Nat Methods 14:417–419
pubmed: 28263959
pmcid: 5600148
doi: 10.1038/nmeth.4197
Peotter J, Kasberg W, Pustova I, Audhya A (2019) COPII-mediated trafficking at the ER/ERGIC interface. Traffic 20:491–503
pubmed: 31059169
pmcid: 6640837
doi: 10.1111/tra.12654
Phuyal S, Djaerff E, Le Roux AL, Baker MJ, Fankhauser D, Mahdizadeh SJ, Reiterer V, Parizadeh A, Felder E, Kahlhofer JC et al (2022) Mechanical strain stimulates COPII-dependent secretory trafficking via Rac1. Embo j 41:e110596
pubmed: 35938214
pmcid: 9475550
doi: 10.15252/embj.2022110596
Plate L, Wiseman RL (2017) Regulating secretory proteostasis through the unfolded protein response: from function to therapy. Trends Cell Biol 27:722–737
pubmed: 28647092
pmcid: 5612838
doi: 10.1016/j.tcb.2017.05.006
Saltzman AL, Pan Q, Blencowe BJ (2011) Regulation of alternative splicing by the core spliceosomal machinery. Genes Dev 25:373–384
pubmed: 21325135
pmcid: 3042160
doi: 10.1101/gad.2004811
Schwer B, Kruchten J, Shuman S (2016) Structure-function analysis and genetic interactions of the SmG, SmE, and SmF subunits of the yeast Sm protein ring. Rna 22:1320–1328
pubmed: 27417296
pmcid: 4986888
doi: 10.1261/rna.057448.116
Shen S, Park JW, Lu ZX, Lin L, Henry MD, Wu YN, Zhou Q, Xing Y (2014) rMATS: robust and flexible detection of differential alternative splicing from replicate RNA-Seq data. Proc Natl Acad Sci USA 111:E5593–E5601
pubmed: 25480548
pmcid: 4280593
doi: 10.1073/pnas.1419161111
Simpson JC, Joggerst B, Laketa V, Verissimo F, Cetin C, Erfle H, Bexiga MG, Singan VR, Hériché JK, Neumann B et al (2012) Genome-wide RNAi screening identifies human proteins with a regulatory function in the early secretory pathway. Nat Cell Biol 14:764–774
pubmed: 22660414
doi: 10.1038/ncb2510
Stadel D, Millarte V, Tillmann KD, Huber J, Tamin-Yecheskel BC, Akutsu M, Demishtein A, Ben-Zeev B, Anikster Y, Perez F et al (2015) TECPR2 cooperates with LC3C to regulate COPII-dependent ER export. Mol Cell 60:89–104
pubmed: 26431026
doi: 10.1016/j.molcel.2015.09.010
Sterne-Weiler T, Weatheritt RJ, Best AJ, Ha KCH, Blencowe BJ (2018) Efficient and accurate quantitative profiling of alternative splicing patterns of any complexity on a laptop. Mol Cell 72:187–200.e186
pubmed: 30220560
doi: 10.1016/j.molcel.2018.08.018
Tang BL (2017) Sec16 in conventional and unconventional exocytosis: working at the interface of membrane traffic and secretory autophagy? J Cell Physiol 232:3234–3243
pubmed: 28160489
doi: 10.1002/jcp.25842
Tillmann KD, Reiterer V, Baschieri F, Hoffmann J, Millarte V, Hauser MA, Mazza A, Atias N, Legler DF, Sharan R et al (2015) Regulation of Sec16 levels and dynamics links proliferation and secretion. J Cell Sci 128:670–682
pubmed: 25526736
Urra H, Dufey E, Avril T, Chevet E, Hetz C (2016) Endoplasmic reticulum stress and the hallmarks of cancer. Trends Cancer 2:252–262
pubmed: 28741511
doi: 10.1016/j.trecan.2016.03.007
Ventura A, Kirsch DG, McLaughlin ME, Tuveson DA, Grimm J, Lintault L, Newman J, Reczek EE, Weissleder R, Jacks T (2007) Restoration of p53 function leads to tumour regression in vivo. Nature 445:661–665
pubmed: 17251932
doi: 10.1038/nature05541
Wallin J, Wilting J, Koseki H, Fritsch R, Christ B, Balling R (1994) The role of Pax-1 in axial skeleton development. Development 120:1109–1121
pubmed: 8026324
doi: 10.1242/dev.120.5.1109
Walter P, Ron D (2011) The unfolded protein response: from stress pathway to homeostatic regulation. Science 334:1081–1086
pubmed: 22116877
doi: 10.1126/science.1209038
Wendler F, Gillingham AK, Sinka R, Rosa-Ferreira C, Gordon DE, Franch-Marro X, Peden AA, Vincent JP, Munro S (2010) A genome-wide RNA interference screen identifies two novel components of the metazoan secretory pathway. EMBO J 29:304–314
pubmed: 19942856
doi: 10.1038/emboj.2009.350
Wilhelmi I, Kanski R, Neumann A, Herdt O, Hoff F, Jacob R, Preußner M, Heyd F (2016) Sec16 alternative splicing dynamically controls COPII transport efficiency. Nat Commun 7:12347
pubmed: 27492621
pmcid: 4980449
doi: 10.1038/ncomms12347
Yeo G, Burge CB (2004) Maximum entropy modeling of short sequence motifs with applications to RNA splicing signals. J Comput Biol 11:377–394
pubmed: 15285897
doi: 10.1089/1066527041410418
Zahoor M, Farhan H (2018) Crosstalk of autophagy and the secretory pathway and its role in diseases. Int Rev Cell Mol Biol 337:153–184
pubmed: 29551160
doi: 10.1016/bs.ircmb.2017.12.004
Zheng Z, Zhang X, Huang B, Liu J, Wei X, Shan Z, Wu H, Feng Z, Chen Y, Fan S et al (2021) Site-1 protease controls osteoclastogenesis by mediating LC3 transcription. Cell Death Differ 28:2001–2018
pubmed: 33469231
pmcid: 8184842
doi: 10.1038/s41418-020-00731-6