ArticleFrontiers in genetics2012
Discovery of Novel DENN Proteins: Implications for the Evolution of Eukaryotic Intracellular Membrane Structures and Human Disease.
Article in Frontiers in genetics, 2012. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 164 papers, 1 of them a synthesis that pooled it.
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Who cites it
164 citing papers in PubMed, 1 synthesis or guideline pooled it, 237 citations in OpenAlex.
- C9orf72 and UNC13A are shared risk loci for amyotrophic lateral sclerosis and frontotemporal dementia: a genome-wide meta-analysis.Annals of neurology · 2014Pooled it
- Avl9 defines a family of DENN domain GTPase-activating proteins.The Journal of cell biology · 2026Article
- The DENN Protein SMD1 Forms a Signalling Hub With Rab GTPase YPT1 to Regulate Diverse Biological Processes in Phytopathogenic Fungi and Serves as a HIGS Target for Crop Protection.Molecular plant pathology · 2026Article
- PU.1 restores microglial dysfunction caused by C9ORF72 repeat expansions in neural organoids.Brain : a journal of neurology · 2026Article
- Avl9 defines a family of GTPase-activating proteins that regulate diverse cell biological functions.bioRxiv : the preprint server for biology · 2026Article
- Eukaryote-Wide Distribution of a Family of Longin Domain-Containing GAP Complexes for Small GTPases.Traffic (Copenhagen, Denmark) · 2025Article
- Characterization of a novel zebrafish model ofBrain communications · 2025Article
- Action and therapeutic targets of folliculin interacting protein 1: a novel signaling mechanism in redox regulation.Frontiers in cell and developmental biology · 2025Review
- The Genomic Signature and Transcriptional Response of Metal Tolerance in Brown Trout Inhabiting Metal-Polluted Rivers.Molecular ecology · 2025Article
- C9orf72-Associated Dipeptide Repeat Expansions Perturb ER-Golgi Vesicular Trafficking, Inducing Golgi Fragmentation and ER Stress, in ALS/FTD.Molecular neurobiology · 2024Article
- Poly-GP accumulation due to C9orf72 loss of function induces motor neuron apoptosis through autophagy and mitophagy defects.Autophagy · 2024Article
- Apoptosis and Oxidative Stress in Human Intestinal Epithelial Caco-2 Cells Caused by Marine Phycotoxin Azaspiracid-2.Toxins · 2024Article
- Aberrant protein aggregation in amyotrophic lateral sclerosis.Journal of neurology · 2024Review
- ALS-linked C9orf72-SMCR8 complex is a negative regulator of primary ciliogenesis.Proceedings of the National Academy of Sciences of the United States of America · 2023Article
- C9orf72-catalyzed GTP loading of Rab39A enables HOPS-mediated membrane tethering and fusion in mammalian autophagy.Nature communications · 2023Article
- Article
- DENND3 p.L708V activating variant is involved in the pathogenesis of hereditary hemochromatosis via the RAB12/TFR2 signaling pathway.Hepatology international · 2023Article
- C9ORF72 suppresses JAK-STAT mediated inflammation.iScience · 2023Article
- Article
- Divergent Evolution of Early Terrestrial Fungi Reveals the Evolution of Mucormycosis Pathogenicity Factors.Genome biology and evolution · 2023Article
104 more citing papers are in PubMed but not listed here.
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Authors and funding
4 authors at 3 institutions in 1 country.
Funding
Abstract
The tripartite DENN module, comprised of a N-terminal longin domain, followed by DENN, and d-DENN domains, is a GDP-GTP exchange factor (GEFs) for Rab GTPases, which are regulators of practically all membrane trafficking events in eukaryotes. Using sequence and structure analysis we identify multiple novel homologs of the DENN module, many of which can be traced back to the ancestral eukaryote. These findings provide unexpected leads regarding key cellular processes such as autophagy, vesicle-vacuole interactions, chromosome segregation, and human disease. Of these, SMCR8, the folliculin interacting protein-1 and 2 (FNIP1 and FNIP2), nitrogen permease regulator 2 (NPR2), and NPR3 are proposed to function in recruiting Rab GTPases during different steps of autophagy, fusion of autophagosomes with the vacuole and regulation of cellular metabolism. Another novel DENN protein identified in this study is C9ORF72; expansions of the hexanucleotide GGGGCC in its first intron have been recently implicated in amyotrophic lateral sclerosis (ALS) and fronto-temporal dementia (FTD). While this mutation is proposed to cause a RNA-level defect, the identification of C9ORF72 as a potential DENN-type GEF raises the possibility that at least part of the pathology might relate to a specific Rab-dependent vesicular trafficking process, as has been observed in the case of some other neurological conditions with similar phenotypes. We present evidence that the longin domain, such as those found in the DENN module, are likely to have been ultimately derived from the related domains found in prokaryotic GTPase-activating proteins of MglA-like GTPases. Thus, the origin of the longin domains from this ancient GTPase-interacting domain, concomitant with the radiation of GTPases, especially of the Rab clade, played an important role in the dynamics of eukaryotic intracellular membrane systems.
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Registered trials
Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.