vps29

To successfully infect, viruses must respond to cues that promote their genome delivery into host cells. These keys to virus entry frequently reside inside endocytic vesicles. In a recent mBio article, Poston et al. (D. Poston, Y. Weisblum, A. Hobbs, and P. D. Bieniasz, mBio 13:e0300221, 2022, https://doi.org/10.1128/mbio.03002-21) identified and characterized protein complexes generating endocytic environments favorable for virus entry. These included retromer-associated vacuolar protein sorting 29 (VPS29) proteins...

The mammalian retromer consists of subunits VPS26 (either VPS26A or VPS26B), VPS29 and VPS35, and a loosely associated sorting nexin (SNX) heterodimer or a variety of other SNX proteins. Despite involvement in yeast and mammalian cell trafficking, the role of retromer in development is poorly understood, and its impact on primary ciliogenesis remains unknown. Using CRISPR/Cas9 editing, we demonstrate that vps-26-knockout worms have reduced brood sizes, impaired vulval development and decreased body length, all of which have been linked to ciliogenesis defects...

BACKGROUND: Although immune checkpoint inhibitor (ICI) is regarded as a breakthrough in cancer therapy, only a limited fraction of patients benefit from it. Cancer stemness can be the potential culprit in ICI resistance, but direct clinical evidence is lacking. METHODS: Publicly available scRNA-Seq datasets derived from ICI-treated patients were collected and analyzed to elucidate the association between cancer stemness and ICI response. A novel stemness signature (Stem...

Commander complex is a 16-protein complex that plays multiple roles in various intracellular events in endosomal cargo and in the regulation of cell homeostasis, cell cycle and immune response. It consists of COMMD1-10, CCDC22, CCDC93, DENND10, VPS26C, VPS29, and VPS35L. These proteins are expressed ubiquitously in the human body, and they have been linked to diseases including Wilson's disease, atherosclerosis, and several types of cancer. In this review we describe the function of the commander complex in endosomal cargo and summarize the individual known roles of COMMD proteins in cell signaling and cancer...

Vps35 (vacuolar protein sorting 35) is a key component of retromer that consists of Vps35, Vps26, and Vps29 trimers, and sortin nexin dimers. Dysfunctional Vps35/retromer is believed to be a risk factor for development of various neurodegenerative diseases. Vps35Neurod6 mice, which selectively knock out Vps35 in Neurod6-Cre+ pyramidal neurons, exhibit age-dependent impairments in terminal differentiation of dendrites and axons of cortical and hippocampal neurons, neuro-degenerative pathology (i.e., increases in P62 and Tdp43 (TAR DNA-binding protein 43) proteins, cell death, and reactive gliosis), and neonatal death...

BACKGROUND: In our previous studies, we demonstrated that the accumulation of carotenoids in QN Orange scallops might be regulated by the vacuolar protein sorting 29 (VPS29) gene. VPS genes are involved in pigments accumulation (including carotenoids) in some species and VPS29 is known as the core component of the membrane transport complex Retromer. However, the possible mechanism of carotenoids accumulation underlying the VPS29 remains unexplored. This study aimed to further elucidate the roles of VPS29 in the carotenoid deposition...

Retromer is a master regulator of cargo retrieval from endosomes, which is critical for many cellular processes including signaling, immunity, neuroprotection, and virus infection. The retromer core (VPS26/VPS29/VPS35) is present on cargo-transporting, tubular carriers along with a range of sorting nexins. Here, we elucidate the structural basis of membrane tubulation and coupled cargo recognition by metazoan and fungal retromer coats assembled with the non-Bin1/Amphiphysin/Rvs (BAR) sorting nexin SNX3 using cryo-electron tomography...

Biogenesis of viral replication organelles (VROs) is critical for replication of positive-strand RNA viruses. In this work, we demonstrate that tomato bushy stunt virus (TBSV) and the closely related carnation Italian ringspot virus (CIRV) hijack the retromer to facilitate building VROs in the surrogate host yeast and in plants. Depletion of retromer proteins, which are needed for biogenesis of endosomal tubular transport carriers, strongly inhibits the peroxisome-associated TBSV and the mitochondria-associated CIRV replication in yeast and in planta...

Retromer (VPS26/VPS35/VPS29) is a highly conserved eukaryotic protein complex that localizes to endosomes to sort transmembrane protein cargoes into vesicles and elongated tubules. Retromer mediates retrieval pathways from endosomes to the trans-Golgi network in all eukaryotes and further facilitates recycling pathways to the plasma membrane in metazoans. In cells, retromer engages multiple partners to orchestrate the formation of tubulovesicular structures, including sorting nexin (SNX) proteins, cargo adaptors, GTPases, regulators, and actin remodeling proteins...

Human retromer, a heterotrimer of VPS26 (VPS26A or VPS26B), VPS35 and VPS29, orchestrates the endosomal retrieval of internalised cargo and promotes their cell surface recycling, a prototypical cargo being the glucose transporter GLUT1 (also known as SLC2A1). The role of retromer in the retrograde sorting of the cation-independent mannose 6-phosphate receptor (CI-MPR, also known as IGF2R) from endosomes back to the trans -Golgi network remains controversial. Here, by applying knocksideways technology, we develop a method for acute retromer inactivation...

Amyotrophic Lateral Sclerosis (ALS) is a fatal disease characterized by the degeneration of upper and lower motor neurons (MNs). We find a significant reduction of the retromer complex subunit VPS35 in iPSCs-derived MNs from ALS patients, in MNs from ALS post mortem explants and in MNs from SOD1G93A mice. Being the retromer involved in trafficking of hydrolases, a pathological hallmark in ALS, we design, synthesize and characterize an array of retromer stabilizers based on bis-guanylhydrazones connected by a 1,3-phenyl ring linker...

Parkinson's disease (PD) is a highly prevalent neurodegenerative condition. The disease involves the progressive degeneration of dopaminergic neurons located in the substantia nigra pars compacta. Among late-onset, familial forms of Parkinson are cases with mutations in the PARK17 locus encoding the vacuolar protein sorting 35 (Vps35), a subunit of the retromer complex. The retromer complex is composed of a heterotrimeric protein core (Vps26-Vps35-Vps29). The best-known role of retromer is the retrieval of cargoes from endosomes to the Golgi complex or the plasma membrane...

Substantial genetic liability is shared across psychiatric disorders but less is known about risk variants that are specific to a given disorder. We used multi-trait conditional and joint analysis (mtCOJO) to adjust GWAS summary statistics of one disorder for the effects of genetically correlated traits to identify putative disorder-specific SNP associations. We applied mtCOJO to summary statistics for five psychiatric disorders from the Psychiatric Genomics Consortium-schizophrenia (SCZ), bipolar disorder (BIP), major depression (MD), attention-deficit hyperactivity disorder (ADHD) and autism (AUT)...

We did a comparative analysis of the gene expression profiles of the hippocampus from sleep deprivation and Alzheimer's disease (AD) mice. Differentially expressed genes (DEGs) were identified by comparing the transcriptome profiles of the hippocampus of sleep deprivation or AD mouse models to matched controls. The common DEGs between sleep deprivation and AD were identified by the overlapping analysis, followed by Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) analyses. The results showed that a total of 16 common DEGs showed similar change patterns in both sleep deprivation mice and AD mice...

OBJECTIVE: Most of Down syndrome (DS) patients develop Alzheimer's disease (AD) neuropathology by age 40. Although this increased susceptibility to AD in DS is thought to be primarily due to triplication of the amyloid precursor protein located on chromosome 21, the precise molecular mechanisms are not well understood. Recent evidence has implicated defective protein sorting and trafficking secondary to deficiencies in retromer complex proteins in AD pathogenesis. Thus, the objective of the present study is to assess the retromer complex system in DS...

Retromer, including Vps35, Vps26, and Vps29, is a protein complex responsible for recycling proteins within the endolysosomal pathway. Although implicated in both Parkinson's and Alzheimer's disease, our understanding of retromer function in the adult brain remains limited, in part because Vps35 and Vps26 are essential for development. In Drosophila , we find that Vps29 is dispensable for embryogenesis but required for retromer function in aging adults, including for synaptic transmission, survival, and locomotion...

Metazoan retromer (VPS26/VPS35/VPS29) associates with sorting nexins on endosomal tubules to sort proteins to the trans-Golgi network or plasma membrane. Mechanisms of metazoan retromer assembly remain undefined. We combine single-particle cryoelectron microscopy with biophysical methods to uncover multiple oligomer structures. 2D class averages reveal mammalian heterotrimers; dimers of trimers; tetramers of trimers; and flat chains. These species are further supported by biophysical solution studies. We provide reconstructions of all species, including key sub-structures (∼5 Å resolution)...

The endolysosomal system is a highly dynamic network of membranes for degradation and recycling. During endosomal maturation, cargo molecules destined for lysosomal degradation are progressively concentrated through continuous rounds of fusion and fission reactions concomitant with inbound and outbound membrane fluxes. Of the cargo molecules delivered to endosomes, about two-thirds are rescued from degradation and recycled for reuse. This balance between degradation and recycling is essential to preserve the proteostatic plasticity of the cell under variable physiological demands...

The retromer is a multiprotein complex conserved from yeast to humans, which is involved in intracellular protein trafficking and protein recycling. Selection of cargo proteins transported by the retromer depends on the core retromer subunit composed of the three vacuolar protein sorting (VPS) proteins, namely VPS26, VPS29, and VPS35. To gain a better knowledge of the importance of the plant retromer in protein sorting, we carried out a comparative proteomic and metabolomic analysis of Arabidopsis thaliana seeds from the wild-type and the null-retromer mutant vps29 ...

Retromer is an evolutionarily conserved endosomal trafficking complex that mediates the retrieval of cargo proteins from a degradative pathway for sorting back to the cell surface. To promote cargo recycling, the core retromer trimer of VPS26, VPS29 and VPS35 recognises cargo either directly, or through an adaptor protein, the most well-characterised of which is the PDZ domain-containing sorting nexin SNX27. Neuroligins (NLGs) are postsynaptic trans-synaptic scaffold proteins that function in the clustering of postsynaptic proteins to maintain synaptic stability...