Rab27a co-ordinates actin-dependent transport by controlling organelle-associated motors and track assembly proteins

Alzahofi, Noura; Robinson, Christopher L.; Welz, Tobias; Page, Emma L.; Briggs, Deborah A.; Stainthorp, Amy; Reekes, James; Elbe, David A; Straub, Felix; Tate, Edward W.; Goff, Philip S.; Sviderskaya, Elena V.; Cantero, Marta; Montoliu, Lluı́s; Bailly, Maryse; Kerkhoff, Eugen; Hume, Alistair N.

doi:10.1101/314153

Cited by 7 publications

(18 citation statements)

References 73 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…These data indicate a general function of mitoSPIRE1 in negative regulation of mitochondrial motility. Our results are in contrast to SPIRE function in vesicle transport processes, where SPIRE-organised actin/myosin networks were shown to drive RAB27 and RAB11 vesicle transport (Pfender et al, 2011;Schuh, 2011) (Alzahofi et al, 2020).…”

Section: Loss Of Mitospire1 Function Increases Mitochondrial Motilitycontrasting

confidence: 99%

“…Gene expression analysis failed to detect a transcript that has both alternatively spliced exons (Kollmar et la., 2019). All SPIRE proteins encode an N-terminal kinase non catalytic C-lobe domain (KIND), which interacts with FMN-subgroup formins, a cluster of monomeric globular actin (G-actin) binding Wiskott-Aldrich homolgy 2 (WH2) domains, a myosin 5 globular tail domain binding motif (GTBM), a RAB interaction domain (Alzahofi et al, 2020) consisting of the SPIRE-box, a modified FYVE zinc finger domain (mFYVE), and conserved C-terminal flanking sequences (Kollmar et al, 2019)(Welz and (Fig. 1B).…”

Section: Origin and Expression Of Mitospire1mentioning

confidence: 99%

“…Research on SPIRE function in vesicle transport processes has been complicated in the past by redundant SPIRE1 and SPIRE2 functions (Pfender et al, 2011) (Alzahofi et al, 2020). The mitochondrial SPIRE1 function, however, cannot be compensated by SPIRE2 since SPIRE2 does not localise to mitochondria (Kollmar et al, 2019).…”

Section: Generation Of a Splice-variant Specific Mitospire1 Knockout mentioning

confidence: 99%

“…Vesicular SPIRE proteins function in organising actin/myosin networks to drive vesicle transport processes towards the cell periphery (Pfender et al, 2011;Schuh, 2011) (Alzahofi et al, 2020). The nature of the transport pathways is determined by the interaction of SPIRE proteins with RAB GTPases, vesicle membranes, and MYO5 motor proteins (Pylypenko et al, 2016;Tittel et al, 2015) (Kollmar et al, 2019;Alzahofi et al, 2020). The SPIRE1 exon 13encoded sequences anchor mitoSPIRE1 to the mitochondrial membrane (Manor et al, 2015)( Fig.…”

Section: Loss Of Mitospire1 Function Increases Mitochondrial Motilitymentioning

confidence: 99%

“…The mitochondrial SPIRE1 isoform was originally termed SPIRE1C (Manor et al, 2015) and has been renamed here in accordance with its discoverer Uri Manor to mitoSPIRE1, because there an unrelated C-terminal Drosophila splice variant named SpireC previously existed (Rosales-Nieves et al, 2006). SPIRE protein function is best studied in vesicle transport processes, where the mammalian SPIRE1 and SPIRE2 proteins organise actin filament/myosin 5 networks at the vesicle membranes, which transport RAB11 vesicles to the oocyte cortex in mice (Pfender et al, 2011;Schuh, 2011) and, in the case of melanocytes, mediate a centrifugal dispersion of RAB27 melanosomes (Alzahofi et al, 2020). Both vesicle transport processes are driven by MYO5 motor proteins (MYO5B in oocytes, MYO5A in melanocytes).…”

Section: Introductionmentioning

confidence: 99%

See 4 more Smart Citations

The SPIRE1 actin nucleator coordinates actin/myosin functions in the regulation of mitochondrial motility

Straub

Welz

Alberico

et al. 2020

Preprint

Self Cite

View full text Add to dashboard Cite

statement: The mitochondrial SPIRE1 protein targets myosin 5 motor proteins and formin actin-filament nucleators/elongators towards mitochondria and negatively regulates mitochondrial motility. AbstractSubcellular localisation of mitochondria provides a spatial and temporal organisation for cellular energy demands. Long-range mitochondrial transport is mediated by microtubule tracks and associated dynein and kinesin motor proteins. The actin cytoskeleton has a more versatile role and provides transport, tethering, and anchoring functions. SPIRE actin nucleators organise actin filament networks at vesicle membranes, which serve as tracks for myosin 5 motor protein-driven transport processes. Following alternative splicing, SPIRE1 is targeted to mitochondria. In analogy to vesicular SPIRE functions, we have analysed whether SPIRE1 regulates mitochondrial motility. By tracking mitochondria of living fibroblast cells from SPIRE1 mutant mice and splice-variant specific mitochondrial SPIRE1 knockout mice, we determined that the loss of SPIRE1 function increased mitochondrial motility. The SPIRE1 mutant phenotype was reversed by transient overexpression of mitochondrial SPIRE1, which almost completely inhibited motility. Conserved myosin 5 and formin interaction motifs contributed to this inhibition. Consistently, mitochondrial SPIRE1 targeted myosin 5 motors and formin actin filament generators to mitochondria. Our results indicate that SPIRE1 organises an actin/myosin network at mitochondria, which opposes mitochondrial motility.

show abstract

Section: Loss Of Mitospire1 Function Increases Mitochondrial Motilitycontrasting

confidence: 99%

Section: Origin and Expression Of Mitospire1mentioning

confidence: 99%

Section: Generation Of a Splice-variant Specific Mitospire1 Knockout mentioning

confidence: 99%

Section: Loss Of Mitospire1 Function Increases Mitochondrial Motilitymentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

See 3 more Smart Citations

The SPIRE1 actin nucleator coordinates actin/myosin functions in the regulation of mitochondrial motility

Straub

Welz

Alberico

et al. 2020

Preprint

Self Cite

View full text Add to dashboard Cite

show abstract

Investigating DNA methylation as a potential mediator between pigmentation genes, pigmentary traits and skin cancer

Bonilla

Bertoni

Min

et al. 2020

Preprint

View full text Add to dashboard Cite

BackgroundIncidence rates for melanoma and non-melanoma skin cancer (NMSC), which includes basal cell carcinoma (BCC) and squamous cell carcinoma (SCC), have been steadily increasing in all populations. Populations of European ancestry exhibit the highest rates and therefore, have been widely studied. Pigmentation characteristics are well-known risk factors for skin cancer, particularly fair skin, red hair, blue eyes and the inability to tan. Polymorphisms in established pigmentation-related genes have been associated with these traits and with an increased risk of malignancy. However, the functional relationship between genetic variation and disease is still unclear, with the exception of red hair colour variants in the melanocortin 1 receptor (MC1R) gene. ObjectivesThe aim of this study was to explore the possibility that non-coding pigmentation SNPs are associated with pigmentary traits and skin cancer via DNA methylation (DNAm). Methods and ResultsUsing a meta-GWAS of whole blood DNAm from 36 European cohorts (N=27,750; the Genetics of DNA Methylation Consortium, GoDMC), we found that 19 out of 27 pigmentation-associated SNPs distributed within 10 genes (ASIP, BNC2, IRF4, HERC2, MC1R, OCA2, SLC24A4, SLC24A5, SLC45A2, TYR) were associated with 391 DNAm sites across 30 genomic regions. We selected 25 DNAm sites for further analysis.We examined the effect of the chosen DNAm sites on pigmentation traits, sun exposure phenotypes, and skin cancer, and on gene expression in whole blood. We found an association of decreased DNAm at cg07402062 with red hair in the Avon Longitudinal Study of Parents and Children (ALSPAC), and a strong positive association of DNAm at this and correlated sites with higher expression of SPIRE2. Additionally, we investigated the association of gene expression in skin with pigmentation traits and skin cancer. The expression of ASIP, FAM83C, NCOA6, CDK10, and EXOC2 was associated with hair colour, whilst that of ASIP and CDK10 also had an effect on melanoma and BCC. ConclusionsOur results indicate that DNAm and expression of genes in the 16q24.3 and 20q11.22 regions, deserve to be further investigated as potential mediators of the relationship between genetic variants, pigmentation/sun exposure phenotypes, and some types of skin cancer.We are extremely grateful to all the families who took part in this study, the midwives for their help in recruiting them, and the whole ALSPAC team, which includes interviewers, computer and laboratory technicians, clerical workers, research scientists, volunteers, managers, receptionists and nurses.

show abstract

The actin nucleator Spir-1 is a virus restriction factor that promotes IRF3 activation

Torres

Macilwee

Rashid

et al. 2020

Preprint

View full text Add to dashboard Cite

Characterisation of viral proteins that mediate immune evasion enables identification of host proteins that function in innate immunity and act as viral restriction factors. This is shown here with vaccinia virus (VACV) protein K7. K7 is a virulence factor that inhibits activation of IRF3 and NF-κB and binds the DEAD-box RNA helicase 3 (DDX3). In this study, Spir-1 is characterised as an additional cellular protein bound by K7 during VACV infection. Spir-1 belongs to a family of actin-binding proteins, however its interaction with K7 does not require its actin-binding domains, suggesting a new function. In human and mouse cells lacking Spir-1, IRF3 activation is impaired, whereas, conversely, Spir-1 overexpression enhanced IRF3 activation. Like DDX3, Spir-1 interacts with K7 directly via a diphenylalanine motif that also is required to promote IRF3 activation. The biological importance of Spir-1 in the response to virus infection is shown by enhanced replication/spreading of VACV in Spir-1 knockout cells. Thus Spir-1 is a new viral restriction factor that functions to enhance IRF3 activation.

show abstract

Rab27a co-ordinates actin-dependent transport by controlling organelle-associated motors and track assembly proteins

Cited by 7 publications

References 73 publications

The SPIRE1 actin nucleator coordinates actin/myosin functions in the regulation of mitochondrial motility

The SPIRE1 actin nucleator coordinates actin/myosin functions in the regulation of mitochondrial motility

Investigating DNA methylation as a potential mediator between pigmentation genes, pigmentary traits and skin cancer

The actin nucleator Spir-1 is a virus restriction factor that promotes IRF3 activation

Contact Info

Product

Resources

About