Phylogenetic profiling and cellular analyses of ARL16 reveal roles in traffic of IFT140 and INPP5E

Dewees, Skylar I; Vargová, Romana; Hardin, Katherine R; Turn, Rachel E; Devi, Saroja; Linnert, Joshua; Wolfrum, Uwe; Caspary, Tamara; Eliáš, Marek; Kahn, Richard

doi:10.1091/mbc.e21-10-0509-t

Cited by 13 publications

(11 citation statements)

References 112 publications

(146 reference statements)

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“…While ARL13B can be palmitoylated on cysteine residues near the N-terminus and thereby become anchored in the membrane, it is not clear how ARL3 is retained in cilia, though its local activation by ARL13B may regulate its localization in cilia. We also have recently identified defects in ciliogenesis and ciliary protein content in cells deleted for ARL16 ( Dewees et al. , 2021 ).…”

Section: Introductionmentioning

confidence: 93%

The ARF GAPs ELMOD1 and ELMOD3 act at the Golgi and cilia to regulate ciliogenesis and ciliary protein traffic

Turn

Dewees

et al. 2022

MBoC

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ELMODs are a family of three mammalian paralogs that display GTPase activating protein (GAP) activity towards a uniquely broad array of ADP-ribosylation factor (ARF) family GTPases that includes ARF-like (ARL) proteins. ELMODs are ubiquitously expressed in mammalian tissues, highly conserved across eukaryotes, and ancient in origin, being present in the last eukaryotic common ancestor. We described functions of ELMOD2 in immortalized mouse embryonic fibroblasts (MEFs) in the regulation of cell division, microtubules, ciliogenesis, and mitochondrial fusion. Here, using similar strategies with the paralogs ELMOD1 and ELMOD3, we identify novel functions and locations of these cell regulators and compare them to those of ELMOD2, allowing determination of functional redundancy among the family members. We found strong similarities in phenotypes resulting from deletion of either Elmod1 or Elmod3 and marked differences from those arising in Elmod2 deletion lines. Deletion of either Elmod1 or Elmod3 results in the decreased ability of cells to form primary cilia, loss of a subset of proteins from cilia, and accumulation of some ciliary proteins at the Golgi, predicted to result from compromised traffic from the Golgi to cilia. These phenotypes are reversed upon activating mutant expression of either ARL3 or ARL16, linking their roles to ELMOD1/3 actions.

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Section: Introductionmentioning

confidence: 93%

The ARF GAPs ELMOD1 and ELMOD3 act at the Golgi and cilia to regulate ciliogenesis and ciliary protein traffic

Turn

Dewees

et al. 2022

MBoC

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“…Here, the remarkable flexibility of IFT-A we describe may enable IFT-A to adapt to a spherical membrane. In either scenario, recruitment of IFT-A to membranes is likely to be regulated by exogenous factors, such as TULPs (Badgandi et al, 2017; Mukhopadhyay et al, 2010), CPLANE (Langousis et al, 2022; Toriyama et al, 2016), and small GTPases (Dewees et al, 2022; Langousis et al, 2022).…”

Section: Discussionmentioning

confidence: 99%

IFT-A Structure Reveals Carriages for Membrane Protein Transport into Cilia

Hesketh

Mukhopadhyay

Nakamura

et al. 2022

Preprint

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Intraflagellar transport (IFT) trains are molecular machines that traffic proteins between cilia and the cell body. With a molecular weight over 80 MDa, each IFT train is a dynamic polymer of two large complexes (IFT-A and -B) and motor proteins, posing a formidable challenge to mechanistic understanding. Here, we reconstituted the complete human IFT-A complex and obtained its structure using cryo-EM. Combined with AlphaFold prediction and genome-editing studies, our results illuminate how IFT-A polymerizes; interacts with IFT-B; and uses an array of beta-propeller and TPR domains to create "carriages" of the IFT train that engage TULP adaptor proteins. We show that IFT-A:TULP carriages are essential for cilia localization of diverse membrane proteins, as well as ICK - the key kinase regulating IFT train turnaround. These data establish a structural link between IFT-A's distinct functions, provide a blueprint for the IFT-A train, and shed light on how IFT evolved from a proto-coatomer ancestor.

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“…Signal was frequently observed in the basal body and throughout the intravacuolar network (Figure S6A). Given the potential relationship of ArlX1 with Arl16, and its recent implication in flagellar biogenesis, this could indicate a role for ArlX1 in trafficking to the basal body and/or apical complex (38). ArlX2 had no clear localization pattern, appearing as a series of punctate dots throughout the cell.…”

Section: Resultsmentioning

confidence: 99%

Evolution of lineage-specific trafficking proteins and a novel post-Golgi trafficking pathway in Apicomplexa

Klinger

Jiménez-Ruiz

Mourier

et al. 2022

Preprint

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The Organelle Paralogy Hypothesis (OPH) posits a mechanism to explain the evolution of non-endosymbiotically derived organelles, predicting that lineage-specific pathways organelles should result when identity-encoding membrane trafficking components duplicate and co-evolve. Here we investigate the presence of such lineage-specific membrane-trafficking machinery paralogs in the globally important lineage of parasites, the Apicomplexa. Using a new phylogenetic workflow, we are able to identify 18 novel paralogs of known membrane-trafficking machinery, the emergence of several of which correlate with the presence of new endomembrane organelles in apicomplexans or their larger lineage. Gene coregulation analysis of a large set of membrane-trafficking proteins in Toxoplasma both corroborate known molecular cell biological interactions between characterized machinery and suggest involvement of many of these new components into established pathways for biogenesis of or trafficking to the microneme and rhoptry invasion organelles. Moreover, focused molecular parasitological analysis of the apicomplexan Arf-like small GTPases, and the ArlX3 protein specifically, revealed a novel post-Golgi trafficking pathways involved in delivery of proteins to micronemes and rhoptries, with knock down demonstrating reduced invasion capacity. The totality of our data has identified an unforeseen post-Golgi trafficking pathway in apicomplexans and is consistent with the OPH mechanism acting to produce novel endomembrane pathways or organelles at various evolutionary stages across the Alveolate lineage.

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Phylogenetic profiling and cellular analyses of ARL16 reveal roles in traffic of IFT140 and INPP5E

Abstract: Phylogenetic analyses of ARF family GTPases predict that ARL16 is linked to cilia. This was confirmed using mouse embryonic fibroblasts deleted for ARL16, resulting in defects in Golgi-to-cilium traffic, with accumulation of IFT140 and INPP5E at Golgi.

Cited by 13 publications

References 112 publications

The ARF GAPs ELMOD1 and ELMOD3 act at the Golgi and cilia to regulate ciliogenesis and ciliary protein traffic

The ARF GAPs ELMOD1 and ELMOD3 act at the Golgi and cilia to regulate ciliogenesis and ciliary protein traffic

IFT-A Structure Reveals Carriages for Membrane Protein Transport into Cilia

Evolution of lineage-specific trafficking proteins and a novel post-Golgi trafficking pathway in Apicomplexa

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