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Autophagy Aug 2023Impaired activities and abnormally enlarged structures of endolysosomes are frequently observed in Alzheimer disease (AD) brains. However, little is known about whether...
Impaired activities and abnormally enlarged structures of endolysosomes are frequently observed in Alzheimer disease (AD) brains. However, little is known about whether and how endolysosomal dysregulation is triggered and associated with AD. Here, we show that vacuolar ATPase (V-ATPase) is a hub that mediates proteopathy of oligomeric amyloid beta (Aβ) and hyperphosphorylated MAPT/Tau (p-MAPT/Tau). Endolysosomal integrity was largely destroyed in Aβ-overloaded or p-MAPT/Tau-positive neurons in culture and AD brains, which was a necessary step for triggering neurotoxicity, and treatments with acidic nanoparticles or endocytosis inhibitors rescued the endolysosomal impairment and neurotoxicity. Interestingly, we found that the lumenal ATP6V0C and cytosolic ATP6V1B2 subunits of the V-ATPase complex bound to the internalized Aβ and cytosolic PHF-1-reactive MAPT/Tau, respectively. Their interactions disrupted V-ATPase activity and accompanying endolysosomal activity and induced neurodegeneration. Using a genome-wide functional screen, we isolated a suppressor, HYAL (hyaluronidase), which reversed the endolysosomal dysfunction and proteopathy and alleviated the memory impairment in 3xTg-AD mice. Further, we found that its metabolite hyaluronic acid (HA) and HA receptor CD44 attenuated neurotoxicity in affected neurons via V-ATPase. We propose that endolysosomal V-ATPase is a bona fide proteotoxic receptor that binds to pathogenic proteins and deteriorates endolysosomal function in AD, leading to neurodegeneration in proteopathy. AAV, adeno-associated virus; Aβ, amyloid beta; AD, Alzheimer disease; APP, amyloid beta precursor protein; ATP6V0C, ATPase H+ transporting V0 subunit c; ATP6V1A, ATPase H+ transporting V1 subunit A; ATP6V1B2, ATPase H+ transporting V1 subunit B2; CD44.Fc, CD44-mouse immunoglobulin Fc fusion construct; Co-IP, co-immunoprecipitation; CTSD, cathepsin D; HA, hyaluronic acid; HMWHA, high-molecular-weight hyaluronic acid; HYAL, hyaluronidase; i.c.v, intracerebroventricular; LMWHA, low-molecular-weight hyaluronic acid; NPs, nanoparticles; p-MAPT/Tau, hyperphosphorylated microtubule associated protein tau; PI3K, phosphoinositide 3-kinase; V-ATPase, vacuolar-type H-translocating ATPase; WT, wild-type.
Topics: Mice; Animals; Alzheimer Disease; Amyloid beta-Peptides; Vacuolar Proton-Translocating ATPases; Hyaluronoglucosaminidase; Hyaluronic Acid; Phosphatidylinositol 3-Kinases; Autophagy; tau Proteins; Amyloid beta-Protein Precursor; Carrier Proteins; Mice, Transgenic; Disease Models, Animal
PubMed: 36843263
DOI: 10.1080/15548627.2023.2181614 -
Frontiers in Immunology 2023Cell migration-inducing protein (CEMIP), also known as KIAA1199 and hyaluronan-binding protein involved in hyaluronan depolymerization, is a new member of the... (Review)
Review
Cell migration-inducing protein (CEMIP), also known as KIAA1199 and hyaluronan-binding protein involved in hyaluronan depolymerization, is a new member of the hyaluronidase family that degrades hyaluronic acid (HA) and remodels the extracellular matrix. In recent years, some studies have reported that CEMIP can promote the proliferation, invasion, and adhesion of various tumor cells and can play an important role in bacterial infection and arthritis. This review focuses on the pathological mechanism of CEMIP in a variety of diseases and expounds the function of CEMIP from the aspects of inhibiting cell apoptosis, promoting HA degradation, inducing inflammatory responses and related phosphorylation, adjusting cellular microenvironment, and regulating tissue fibrosis. The diagnosis and treatment strategies targeting CEMIP are also summarized. The various functions of CEMIP show its great potential application value.
Topics: Humans; Hyaluronic Acid; Hyaluronoglucosaminidase; Apoptosis; Arthritis; Cell Movement
PubMed: 37662915
DOI: 10.3389/fimmu.2023.1222425 -
Biomedicine & Pharmacotherapy =... Sep 2023HYBID is a new hyaluronan-degrading enzyme and exists in various cells of the human body. Recently, HYBID was found to over-express in the osteoarthritic chondrocytes... (Review)
Review
HYBID is a new hyaluronan-degrading enzyme and exists in various cells of the human body. Recently, HYBID was found to over-express in the osteoarthritic chondrocytes and fibroblast-like synoviocytes. According to these researches, high level of HYBID is significantly correlated with cartilage degeneration in joints and hyaluronic acid degradation in synovial fluid. In addition, HYBID can affect inflammatory cytokine secretion, cartilage and synovium fibrosis, synovial hyperplasia via multiple signaling pathways, thereby exacerbating osteoarthritis. Based on the existing research of HYBID in osteoarthritis, HYBID can break the metabolic balance of HA in joints through the degradation ability independent of HYALs/CD44 system and furthermore affect cartilage structure and mechanotransduction of chondrocytes. In particular, in addition to HYBID itself being able to trigger some signaling pathways, we believe that low-molecular-weight hyaluronan produced by excess degradation can also stimulate some disease-promoting signaling pathways by replacing high-molecular-weight hyaluronan in joints. The specific role of HYBID in osteoarthritis is gradually revealed, and the discovery of HYBID raises the new way to treat osteoarthritis. In this review, the expression and basic functions of HYBID in joints were summarized, and reveal potential role of HYBID as a key target in treatment for osteoarthritis.
Topics: Humans; Hyaluronic Acid; Mechanotransduction, Cellular; Osteoarthritis; Hyaluronoglucosaminidase; Disease Progression
PubMed: 37364478
DOI: 10.1016/j.biopha.2023.115043 -
Indian Journal of Ophthalmology Jul 2023Cataract surgery ranks among the commonest procedures performed worldwide. Approximately 51% of blindness worldwide is related to cataracts, affecting about 65.2 million... (Review)
Review
Cataract surgery ranks among the commonest procedures performed worldwide. Approximately 51% of blindness worldwide is related to cataracts, affecting about 65.2 million people worldwide and more so in developing countries. Over the years, there has been a significant evolution in the surgical techniques of cataract extraction. The advancement in phacoemulsification machines, phaco-tips, and the availability of ophthalmic viscoelastic devices have played a substantial role in cataract surgery such that they are faster and more controlled than before. Similarly, anesthetic techniques in cataract surgery have advanced significantly from retrobulbar, peribulbar, and sub-Tenon's blocks to topical anesthesia. Though topical anesthesia eliminates the possible complications of injectable anesthesia, it is not suitable for use in uncooperative, anxious patients, pediatric age groups, and patients with cognitive disabilities. Hyaluronidase is an enzyme that breaks down hyaluronic acid in the retrobulbar tissue, facilitating uniform diffusion of the anesthetic drug and hastening the onset of anesthesia and akinesia. Hyaluronidase has been used in the last 80 years successfully as an adjuvant in retrobulbar, peribulbar, and sub-Tenon's blocks. Initially, the hyaluronidase enzyme was animal-derived and of bovine and ovine sources. Recombinant human-derived hyaluronidase, which has lesser allergic reactions, impurities, and toxicity, is now available. There is conflicting evidence regarding the efficacy of hyaluronidase as an adjuvant in retrobulbar and peribulbar blocks. This article summarizes a brief review of the literature on the role of hyaluronidase as an adjuvant in local anesthetic blocks in ophthalmic surgeries.
Topics: Humans; Animals; Cattle; Sheep; Child; Anesthesia, Local; Hyaluronoglucosaminidase; Anesthetics, Local; Cataract Extraction; Cataract; Lidocaine
PubMed: 37417102
DOI: 10.4103/IJO.IJO_2515_22 -
The Journal of Biological Chemistry Sep 2023Transmembrane protein 2 (TMEM2) was originally identified as a membrane-anchored protein of unknown function. We previously demonstrated that TMEM2 can degrade...
Transmembrane protein 2 (TMEM2) was originally identified as a membrane-anchored protein of unknown function. We previously demonstrated that TMEM2 can degrade hyaluronan (HA). Furthermore, we showed that induced global knockout of Tmem2 in adult mice results in rapid accumulation of incompletely degraded HA in bodily fluids and organs, supporting the identity of TMEM2 as a cell surface hyaluronidase. In spite of these advances, no direct evidence has been presented to demonstrate the intrinsic hyaluronidase activity of TMEM2. Here, we directly establish the catalytic activity of TMEM2. The ectodomain of TMEM2 (TMEM2) was expressed as a His-tagged soluble protein and purified by affinity and size-exclusion chromatography. Both human and mouse TMEM2 robustly degrade fluorescein-labeled HA into 5 to 10 kDa fragments. TMEM2 exhibits this HA-degrading activity irrespective of the species of TMEM2 origin and the position of epitope tag insertion. The HA-degrading activity of TMEM2 is more potent than that of HYAL2, a hyaluronidase which, like TMEM2, has been implicated in cell surface HA degradation. Finally, we show that TMEM2 can degrade not only fluorescein-labeled HA but also native high-molecular weight HA. In addition to these core findings, our study reveals hitherto unrecognized confounding factors, such as the quality of reagents and the choice of assay systems, that could lead to erroneous conclusions regarding the catalytic activity of TMEM2. In conclusion, our results demonstrate that TMEM2 is a legitimate functional hyaluronidase. Our findings also raise cautions regarding the choice of reagents and methods for performing degradation assays for hyaluronidases.
Topics: Animals; Humans; Mice; Cell Membrane; Fluoresceins; Hyaluronic Acid; Hyaluronoglucosaminidase; Membrane Proteins
PubMed: 37527776
DOI: 10.1016/j.jbc.2023.105120 -
PeerJ 2024CEMIP is a protein known for inducing cell migration and binding to hyaluronic acid. Functioning as a hyaluronidase, CEMIP primarily facilitates the breakdown of the... (Review)
Review
CEMIP is a protein known for inducing cell migration and binding to hyaluronic acid. Functioning as a hyaluronidase, CEMIP primarily facilitates the breakdown of the extracellular matrix component, hyaluronic acid, thereby regulating various signaling pathways. Recent evidence has highlighted the significant role of CEMIP in different cancers, associating it with diverse pathological states. While identified as a biomarker for several diseases, CEMIP's mechanism in cancer seems distinct. Accumulating data suggests that CEMIP expression is triggered by chemical modifications to itself and other influencing factors. Transcriptionally, chemical alterations to the CEMIP promoter and involvement of transcription factors such as AP-1, HIF, and NF-κB regulate CEMIP levels. Similarly, specific miRNAs have been found to post-transcriptionally regulate CEMIP. This review provides a comprehensive summary of CEMIP's role in various cancers and explores how both transcriptional and post-transcriptional mechanisms control its expression.
Topics: Hyaluronic Acid; Cell Line, Tumor; Hyaluronoglucosaminidase; Gene Expression Regulation; MicroRNAs; Neoplasms
PubMed: 38390387
DOI: 10.7717/peerj.16930 -
Nature Communications Dec 2023Acne is a dermatologic disease with a strong pathologic association with human commensal Cutibacterium acnes. Conspicuously, certain C. acnes phylotypes are associated...
Acne is a dermatologic disease with a strong pathologic association with human commensal Cutibacterium acnes. Conspicuously, certain C. acnes phylotypes are associated with acne, whereas others are associated with healthy skin. Here we investigate if the evolution of a C. acnes enzyme contributes to health or acne. Two hyaluronidase variants exclusively expressed by C. acnes strains, HylA and HylB, demonstrate remarkable clinical correlation with acne or health. We show that HylA is strongly pro-inflammatory, and HylB is modestly anti-inflammatory in a murine (female) acne model. Structural and phylogenic studies suggest that the enzymes evolved from a common hyaluronidase that acquired distinct enzymatic activity. Health-associated HylB degrades hyaluronic acid (HA) exclusively to HA disaccharides leading to reduced inflammation, whereas HylA generates large-sized HA fragments that drive robust TLR2-dependent pathology. Replacing an amino acid, Serine to Glycine near the HylA catalytic site enhances the enzymatic activity of HylA and produces an HA degradation pattern intermediate to HylA and HylB. Selective targeting of HylA using peptide vaccine or inhibitors alleviates acne pathology. We suggest that the functional divergence of HylA and HylB is a major driving force behind C. acnes health- and acne- phenotype and propose targeting of HylA as an approach for acne therapy.
Topics: Humans; Female; Animals; Mice; Hyaluronoglucosaminidase; Skin; Acne Vulgaris; Propionibacterium acnes; Amino Acids
PubMed: 38052825
DOI: 10.1038/s41467-023-43833-8 -
MBio Oct 2023Bacteria such as GBS can cause infections during pregnancy leading to preterm births, stillbirths, and neonatal infections. The interaction between host and bacterial...
Bacteria such as GBS can cause infections during pregnancy leading to preterm births, stillbirths, and neonatal infections. The interaction between host and bacterial factors during infections in the placenta is not fully understood. GBS secretes a hyaluronidase enzyme that is thought to digest host hyaluronan into immunosuppressive disaccharides that dampen TLR2/4 signaling, leading to increased bacterial dissemination and adverse outcomes. In this study, we show that GBS HylB mediates immune suppression and promotes bacterial infection during pregnancy that requires TLR2, TLR4, and IL-10. Understanding the interaction between host and bacterial factors can inform future therapeutic strategies to mitigate GBS infections.
Topics: Pregnancy; Female; Infant, Newborn; Humans; Hyaluronoglucosaminidase; Toll-Like Receptor 2; Interleukin-10; Streptococcus agalactiae; Pregnancy Complications, Infectious; Streptococcal Infections
PubMed: 37747229
DOI: 10.1128/mbio.02049-23 -
Renal Failure Dec 2023Renal dysfunction and disruption of renal endothelial glycocalyx are two important events during septic acute kidney injury (AKI). Here, the role and mechanism of...
BACKGROUND
Renal dysfunction and disruption of renal endothelial glycocalyx are two important events during septic acute kidney injury (AKI). Here, the role and mechanism of hyaluronidase 1 (HYAL1) in regulating renal injury and renal endothelial glycocalyx breakdown in septic AKI were explored for the first time.
METHODS
BALB/c mice were injected with lipopolysaccharide (LPS, 10 mg/kg) to induce AKI. HYAL1 was blocked using lentivirus-mediated short hairpin RNA targeting HYAL1 (LV-sh-HYAL1). Biochemical assays were performed to measure the levels and concentrations of biochemical parameters associated with AKI as well as levels of inflammatory cytokines. Renal pathological lesions were determined by hematoxylin-eosin (HE) staining. Cell apoptosis in the kidney was detected using terminal-deoxynucleoitidyl transferase-mediated nick end labeling (TUNEL) assay. Immunofluorescence and immunohistochemical (IHC) staining assays were used to examine the levels of hyaluronic acid in the kidney. The protein levels of adenosine monophosphate-activated protein kinase (AMPK)/mammalian target of rapamycin (mTOR) signaling, endothelial glycocalyx, and autophagy-associated indicators were assessed by western blotting.
RESULTS
The knockdown of HYAL1 in LPS-subjected mice by LV-sh-HYAL1 significantly reduced renal inflammation, oxidative stress, apoptosis and kidney dysfunction in AKI, as well as alleviated renal endothelial glycocalyx disruption by preventing the release of hyaluronic acid to the bloodstream. Additionally, autophagy-related protein analysis indicated that knockdown of HYAL1 significantly enhanced autophagy in LPS mice. Furthermore, the beneficial actions of HYAL1 blockade were closely associated with the AMPK/mTOR signaling.
CONCLUSION
HYAL1 deficiency attenuates LPS-triggered renal injury and endothelial glycocalyx breakdown in septic AKI in mice.
Topics: Animals; Mice; Acute Kidney Injury; AMP-Activated Protein Kinases; Apoptosis; Glycocalyx; Hyaluronic Acid; Hyaluronoglucosaminidase; Kidney; Lipopolysaccharides; TOR Serine-Threonine Kinases; Mice, Inbred BALB C
PubMed: 37563795
DOI: 10.1080/0886022X.2023.2188966 -
PloS One 2023Hyaluronic acid (HA) is ubiquitously found in biological tissues and mediates wound healing mechanisms after injury by promoting cell migration and proliferation. With...
Hyaluronic acid (HA) is ubiquitously found in biological tissues and mediates wound healing mechanisms after injury by promoting cell migration and proliferation. With the development of tissue-engineered neural therapeutics, including off-the-shelf grafts for peripheral nerve repair, HA is an attractive material for clinical use because of its various biological roles. HA-based biomaterials have been carefully engineered to elicit specific in vivo host responses, however an important design feature that should be considered in these scaffolds is endogenous degradation. Hyaluronidases (HYALs) are the complementary enzymes that are responsible for HA turnover. Although HYAL expression has been widely characterized in various tissues, including the central nervous system, and for different pathologies, there remains a lack of knowledge of HYAL mediated turnover in peripheral nerve tissue. In this work, gene expression of two hyaluronidases, HYAL1 and HYAL2, and HA-binding receptor, CD44, were studied in two injury models: rat sciatic nerve crush and critical gap transection. HYAL2 and CD44 were shown to be upregulated 3 days after crush injury, whereas HYAL1 was upregulated at 3 weeks, which collectively demonstrate temporal patterning of HA breakdown. Additionally, differences were observed between HYAL and HA expression at 3 weeks when compared for both nerve injury models. The activity of HYAL in peripheral nerve tissue was determined to be approximately 0.11 μmol/min, which could be used to further model HA-based biomaterial breakdown for peripheral nerve applications. Overall, this work provides a landscape of HA turnover in peripheral nerve that can be used for future neural applications.
Topics: Animals; Rats; Peripheral Nerve Injuries; Hyaluronoglucosaminidase; Sciatic Nerve; Biocompatible Materials; Cell Movement; Hyaluronic Acid
PubMed: 37616240
DOI: 10.1371/journal.pone.0289956