Biology subjects

Islam, P.

Publications and source records attributed to Islam, P..

6 recordsLinked to original sources

bioRxiv2025

P-Rex1 Limits the Agonist-Induced Internalisation of GPCRs Independently of its Rac-GEF Activity

The Rac-GEF P-Rex1 mediates GPCR signalling by activating the small GTPase Rac. We show here that P-Rex1 also controls GPCR trafficking. P-Rex1 inhibits the agonist-stimulated internalisation of the GPCR S1PR1 independently of its Rac-GEF activity, through its PDZ, DEP and IP4P domains. P-Rex1 also limits the agonist-induced trafficking of CXCR4, PAR4, and GLP1R, but does not control steady-state GPCR levels, nor the agonist-induced internalisation of the RTKs PDGFR and EGFR. P-Rex1 blocks the phosphorylation required for GPCR internalisation. P-Rex1 binds Grk2, both in vitro and in cells, but does not appear to regulate Grk2 activity. We propose that P-Rex1 limits the agonist-induced internalisation of GPCRs through its interaction with Grk2 to maintain high levels of active GPCR at the plasma membrane. Therefore, P-Rex1 plays a dual role in promoting GPCR responses, by controlling GPCR trafficking through an adaptor function as well as by mediating GPCR signalling through its Rac-GEF activity. HighlightsO_LIP-Rex1 controls GPCR trafficking, independently of its Rac-GEF activity C_LIO_LIP-Rex1 limits the agonist-induced internalisation of S1PR1, CXCR4, PAR4 and GLP1R C_LIO_LIP-Rex1 does not control steady-state GPCR levels, or PDGFR and EGFR trafficking C_LIO_LIP-Rex1 binds Grk2 and inhibits the phosphorylation required for GPCR internalisation C_LI eTOC blurbP-Rex1 activates Rac downstream of GPCRs to regulate processes ranging from innate immunity to neuronal plasticity, its deregulation contributing to cancer. Here, Baker et al. show that P-Rex1 also controls GPCR trafficking, limiting agonist-induced GPCR internalisation through an adaptor function. Thus, P-Rex1 promotes GPCR responses in a dual manner. Graphical Abstract O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=200 SRC="FIGDIR/small/648762v1_ufig1.gif" ALT="Figure 1"> View larger version (54K): org.highwire.dtl.DTLVardef@20e1e2org.highwire.dtl.DTLVardef@cdd416org.highwire.dtl.DTLVardef@11f2a35org.highwire.dtl.DTLVardef@10c2b49_HPS_FORMAT_FIGEXP M_FIG C_FIG

cell biology↗

bioRxiv2023

Rebalancing the motor circuit restores movement in a Caenorhabditis elegans model for TDP-43-toxicity

Amyotrophic lateral sclerosis (ALS) and frontotemporal dementia are caused by the abnormal accumulation of TAR DNA-binding protein 43 (TDP-43) in the cytoplasm of neurons. How TDP-43 accumulation leads to disease symptoms is not well-characterized. Here, we use a C. elegans model for TDP-43-induced toxicity to identify the biological mechanisms that lead to disease-related phenotypes. By applying deep behavioral phenotyping, we established a phenotypic fingerprint of TDP-43 worms. This fingerprint was compared to that of 294 C. elegans mutants, in which genes were mutated that are important for nervous system and muscle functioning. By using a computational clustering approach, we found that the release of acetylcholine and GABA was the primary defect in TDP-43 worms. We then functionally dissected the neuromuscular circuit to show that GABA transmission was more severely diminished compared to acetylcholine. Whereas the loss of GABA transmission was caused by a profound loss of GABA synapses, acetylcholine neurons appeared to be functionally silenced. Enhancing functional output of repressed acetylcholine neurons at the level of G-protein coupled receptors or through optogenetic stimulation restored neurotransmission, but inefficiently rescued locomotion. Surprisingly, rebalancing the excitatory and inhibitory input by simultaneous stimulation of GABA and acetylcholine input into muscles not only synergized the effects of boosting individual neurotransmitter systems, but instantaneously improved movement. Our results suggest that interventions accounting for the altered connectome may be more efficient in restoring motor function than those solely focusing on diseased neuron populations.

cell biology↗

bioRxiv2020

Transgelin: A New Gene Involved in LDL Endocytosis Identified by a Genome-wide CRISPR-Cas9 Screen

To identify new genes involved in the cellular uptake of low-density lipoprotein (LDL), we applied a novel whole genome CRISPR/Cas9 knockout-screen on HepG2 cell lines. We identified TAGLN (transgelin), an actin-binding protein, as a new gene involved in LDL endocytosis. In silico validation demonstrated that genetically predicted differences in expression of TAGLN in human populations were associated with plasma lipids (triglycerides, total cholesterol, HDL, and LDL cholesterol) in the Global Lipids Genetics Consortium and lipid-related phenotypes in the UK Biobank. Decreased cellular LDL uptake observed in TAGLN-knockout cells due to decreased LDL receptor internalization, led to alterations in cellular cholesterol content and compensatory changes in cholesterol biosynthesis. Transgelin was also shown to be involved in the actin-dependent phase of clathrin-mediated endocytosis of other cargo besides LDL. The identification of novel genes involved in LDL uptake may improve the diagnosis of hypercholesterolemia and provide future therapeutic targets for the prevention of cardiovascular disease.

cell biology↗

bioRxiv2020

A C. elegans model of C9orf72-associated ALS/FTD uncovers a conserved role for eIF2D in RAN translation

A hexanucleotide repeat expansion GGGGCC in the noncoding region of C9orf72 is the most common cause of inherited amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD). Potentially toxic dipeptide repeats (DPRs) are synthesized from the GGGGCC sequence via repeat associated non-AUG (RAN) translation. We developed C. elegans models that express, either ubiquitously or exclusively in neurons, a transgene with 75 GGGGCC repeats flanked by intronic C9orf72 sequence. The worms generate DPRs (poly-glycine-alanine [poly-GA], poly-glycine-proline [poly-GP]) and display neurodegeneration, locomotor and lifespan defects. Mutation of a non-canonical translation-initiating codon (CUG) upstream of the repeats blocked poly-GA production and ameliorated disease, suggesting poly-GA is pathogenic. Importantly, eukaryotic translation initiation factor 2D (eif-2D/eIF2D) was necessary for RAN translation. Genetic removal of eif-2D increased lifespan in both C. elegans models. In vitro findings in human cells demonstrated a conserved role for eif-2D/eIF2D in RAN translation that could be exploited for ALS and FTD therapy.

neuroscience↗

bioRxiv2020

Establishment and maintenance of motor neuron identity via temporal modularity in terminal selector function

Terminal selectors are transcription factors (TFs) that establish during development and maintain throughout life post-mitotic neuronal identity. We previously showed that UNC-3/Ebf, the terminal selector of C. elegans cholinergic motor neurons (MNs), acts indirectly to prevent alternative neuronal identities (Feng et al., 2020). Here, we globally identify the direct targets of UNC-3. Unexpectedly, we find that the suite of UNC-3 targets in MNs is modified across different life stages, revealing "temporal modularity" in terminal selector function. In all larval and adult stages examined, UNC-3 is required for continuous expression of various protein classes (e.g., receptors, transporters) critical for MN function. However, only in late larvae and adults, UNC-3 is required to maintain expression of MN-specific TFs. Minimal disruption of UNC-3s temporal modularity via genome engineering affects locomotion. Another C. elegans terminal selector (UNC-30/Pitx) also exhibits temporal modularity, supporting the potential generality of this mechanism for the control of neuronal identity.

developmental biology↗

bioRxiv2019

A terminal selector prevents a Hox transcriptional switch to safeguard motor neuron identity throughout life

Nervous system function critically relies on continuous expression of neuron type-specific terminal identity features, such as neurotransmitter receptors, ion channels and neuropeptides. How individual neuron types select such features during development and maintain them throughout life is poorly understood. Here, we report an unconventional mechanism that enables cholinergic motor neurons (MNs) in the C. elegans ventral nerve cord to select and maintain their distinct terminal identity features. The conserved terminal selector UNC-3 (Collier/Ebf) UNC-3 is continuously required not only to promote cholinergic MN features, but also to prevent expression of \"unwanted\" terminal identity features normally reserved for other neuron types. Mechanistically, this dual function is achieved by the ability of UNC-3 to prevent a switch in the transcriptional targets of the Hox protein LIN-39 (Scr/Dfd/Hox4-5). The strategy of a terminal selector preventing a Hox transcriptional switch may constitute a general principle for safeguarding neuronal terminal identity features throughout life.

developmental biology↗