Cilia and autophagy

Tumor Treating Fields (TTFields) extend the survival of glioblastoma (GBM) patients by interfering with a broad range of tumor cellular processes. Among these, TTFields disrupt primary cilia stability on GBM cells. Here we asked if concomitant treatment of TTFields with other agents that interfere with GBM ciliogenesis further suppress GBM cell proliferation in vitro. Aurora kinase A (AURKA) promotes both cilia disassembly and GBM growth. Inhibitors of AURKA, such as Alisertib, inhibit cilia disassembly and increase ciliary frequency in various cell types...

Autosomal dominant polycystic kidney disease (ADPKD) occurs when the proteins Polycystin-1 (PC1, PKD1 ) and Polycystin-2 (PC2, PKD2 ) contain mutations. PC1 is a large membrane receptor that can interact and form a complex with the calcium-permeable cation channel PC2. This complex localizes to the plasma membrane, primary cilia and ER. Dysregulated calcium signalling and consequential alterations in downstream signalling pathways in ADPKD are linked to cyst formation and expansion; however, it is not completely understood how PC1 and PC2 regulate calcium signalling...

Recurrent miscarriage is used to refer to more than three pregnancy failures before 20 weeks of gestation. Defective trophoblast cell growth and invasion are frequently observed in recurrent miscarriage. Several microRNAs (miRs), including miR‑155‑5p, are aberrantly upregulated in recurrent miscarriage; however, the underlying molecular mechanisms remain unclear. The centrosome orchestrates microtubule networks and coordinates cell cycle progression. In addition, it is a base for primary cilia, which are antenna‑like organelles that coordinate signaling during development and growth...

Mitochondria provide energy for all cellular processes, including reactions associated with cell cycle progression, DNA damage repair, and cilia formation. Moreover, mitochondria participate in cell fate decisions between death and survival. Nek family members have already been implicated in DNA damage response, cilia formation, cell death, and cell cycle control. Here, we discuss the role of several Nek family members, namely Nek1, Nek4, Nek5, Nek6, and Nek10, which are not exclusively dedicated to cell cycle-related functions, in controlling mitochondrial functions...

Recent Studies have shown that the formation of the primary cilium is associated with a specific cellular organelle known as the midbody remnant(MBR), which is a point-like organelle formed by shedding of the midbody at the end of mitosis. MBRs move along the cell surface close to the center body, and regulate it to form primary cilia at the top of centriole. Primary cilia can act as an organelle to inhibit tumorigenesis, and it is lost in a variety of tumors. Studies have shown that the accumulation of MBRs in tumor cells affects ciliogenesis; in addition, both MBRs and primary cilia are degraded in tumor cells through the autophagy pathway, and MBRs can also transfer tumor signaling pathway factors to primary cilia affecting tumorigenesis...

Approximately half of the familial cases of amyotrophic lateral sclerosis (ALS) and frontal temporal dementia (FTD) are attributed to the abnormal GGGGCC repeat expansion within the first intron of C9orf72 , potentializing C9orf72 and its product as the most promising target for ALS therapeutics. Nevertheless, the biological function of C9orf72 remains unclear. Previously, we reported that C9orf72 and its binding partner, SMCR8, form a GTPase-activating protein (GAP) complex, which is proposed to regulate membrane trafficking and autophagy...

The multisubunit HOPS tethering complex is a well-established regulator of lysosome fusion with late endosomes and autophagosomes. However, the role of the HOPS complex in other stages of endo-lysosomal trafficking is not well understood. To address this, we made HeLa cells knocked out for the HOPS-specific subunits Vps39 or Vps41, or the HOPS-CORVET-core subunits Vps18 or Vps11. In all four knockout cells we found that endocytosed cargos were trapped in enlarged endosomes that clustered in the perinuclear area...

Human pluripotent stem cell-derived kidney organoids offer unprecedented opportunities for studying polycystic kidney disease (PKD), which still has no effective cure. Here, we developed both in vitro and in vivo organoid models of PKD that manifested tubular injury and aberrant upregulation of renin-angiotensin aldosterone system. Single-cell analysis revealed that a myriad of metabolic changes occurred during cystogenesis, including defective autophagy. Experimental activation of autophagy via ATG5 overexpression or primary cilia ablation significantly inhibited cystogenesis in PKD kidney organoids...

Centriolar satellites are multiprotein aggregates that orbit the centrosome and govern centrosome homeostasis and primary cilia formation. In contrast to the scaffold PCM1, which nucleates centriolar satellites and has been linked to microtubule dynamics, autophagy, and intracellular trafficking, the functions of its interactant CEP131 beyond ciliogenesis remain unclear. Using a knockout strategy in a non-ciliary T-cell line, we report that, although dispensable for centriolar satellite assembly, CEP131 participates in optimal tubulin glycylation and polyglutamylation, and microtubule regrowth...

Phosphoinositides are a minor group of membrane-associated phospholipids that are transiently generated on the cytoplasmic leaflet of many organelle membranes and the plasma membrane. There are seven functionally distinct phosphoinositides, each derived via the reversible phosphorylation of phosphatidylinositol in various combinations on the inositol ring. Their generation and termination is tightly regulated by phosphatidylinositol-kinases and -phosphatases. These enzymes can function together in an integrated and coordinated manner, whereby the phosphoinositide product of one enzyme may subsequently serve as a substrate for another to generate a different phosphoinositide species...

Autophagy is a fundamental catabolic process whereby excessive or damaged cytoplasmic components are degraded through lysosomes to maintain cellular homeostasis. Studies of mTOR signaling have revealed that mTOR controls biomass generation and metabolism by modulating key cellular processes, including protein synthesis and autophagy. Primary cilia, the assembly of which depends on kinesin molecular motors, serve as sensory organelles and signaling platforms. Given these pathways' central role in maintaining cellular and physiological homeostasis, a connection between mTOR and primary cilia signaling is starting to emerge in a variety of diseases...

Chronic obstructive pulmonary disease (COPD) is a common chronic respiratory illness. It arises from emphysema and chronic bronchitis and is characterized by progressive and irreversible airflow limitation and chronic inflammation of the lungs, which eventually progresses to pulmonary hypertension, chronic pulmonary heart disease and respiratory failure. Autophagy is a highly conserved cellular homeostasis maintenance mechanism that involves the transport of damaged organelles and proteins to lysosomes for destruction...

Mitochondrial autophagy plays a contributary role in the pathogenesis of retina degeneration (RD). ZYAN1 is a novel proline hydroxylase domain (PHD) inhibitor that can enhance the expression of hypoxia-inducible factor 1-alpha (HIF-1α). This study investigated whether ZYAN1 could alleviate progressive photoreceptor loss and oxidative damage in a pharmacologically induced RD model via the modulation of mitophagy. ZYAN1 was injected into the vitreous body of the RD model, and the retinal autophagy level was analyzed...

Cancer whose major problems are metastasis, treatment resistance, and recurrence is the leading cause of death worldwide. Tumor-initiating stem cells (TiSCs) are a subset of the tumor population responsible for tumor resistance and relapse. Understanding the characteristics and shared features between tumor-initiating stem cells (TiSCs) and long-lived postmitotic cells may hold a key to better understanding the biology of cancer. Postmitotic cells have exited the cell cycle and are transitioned into a non-dividing and terminally differentiated state with a specialized function within a tissue...

Recurrent miscarriage is defined as more than three pregnancy failures occurring before 20 weeks of gestation. Poor differentiation of the endometrial stroma or defective trophoblast cell invasion at the maternal-fetal interface leads to recurrent miscarriages. Several miRNAs, including miR-20b-5p, are aberrantly regulated in recurrent miscarriages; however, the underlying molecular mechanisms remain unclear. Primary cilia are antenna-like organelles that coordinate signaling during development and differentiation...

TP53 and RB1 loss-of-function mutations are common in osteosarcoma. During development, combined loss of TP53 and RB1 function leads to downregulation of autophagy and the aberrant formation of primary cilia, cellular organelles essential for the transmission of canonical Hedgehog (Hh) signaling. Excess cilia formation then leads to hypersensitivity to Hedgehog (Hh) ligand signaling. In mouse and human models, we now show that osteosarcomas with mutations in TP53 and RB1 exhibit enhanced ligand-dependent Hh pathway activation through Smoothened (SMO), a transmembrane signaling molecule required for activation of the canonical Hh pathway...

Autosomal-Dominant Polycystic Kidney Disease (ADPKD) is a monogenic disorder initiated by mutations in either PKD1 or PKD2 genes, responsible for encoding polycystin 1 and polycystin 2, respectively. These proteins are primarily located within the primary cilia. The disease follows an inexorable progression, leading most patients to severe renal failure around the age of 50, and extra-renal complications are frequent. A cure for ADPKD remains elusive, but some measures can be employed to manage symptoms and slow cyst growth...

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The Schlemm's canal (SC) is a circular, lymphatic-like vessel located at the limbus of the eye that participates in the regulation of aqueous humor drainage to control intraocular pressure (IOP). Circumferential flow of aqueous humor within the SC lumen generates shear stress, which regulates SC cell behaviour. Using biochemical analysis and real-time live cell imaging techniques, we have investigated the activation of autophagy in SC cells by shear stress. We report, for the first time, the primary cilium (PC)-dependent activation of autophagy in SC cells in response to shear stress...

Cilia are microtubule-based organelles that project from the cell surface with motility or sensory functions. Primary cilia work as antennae to sense and transduce extracellular signals. Cilia critically control proliferation by mediating cell-extrinsic signals and by regulating cell cycle entry. Recent studies have shown that primary cilia and their associated proteins also function in autophagy and genome stability, which are important players in oncogenesis. Abnormal functions of primary cilia may contribute to oncogenesis...