Endoscopic Endonasal Trans-Sphenoidal Minimally Invasive Pituitary Surgery with Image Guided Navigation System (Igns): Learning Experience of Ent Surgeon: First Author.

Introduction- Endoscopic minimally invasive pituitary surgery (MIPS) is advantageous over microscopic technique, as it provides superior close up, wide angle view of surgical target area. Image guided navigation system (IGNS) guides the surgeon to localize the lesion. In the present study we analyzed the Image Guided Surgical procedure and outcome of Endoscopic minimally invasive pituitary surgery and shared our experiences regarding disease clearance. MATERIALS AND METHODS: During the period of April 2015 to August 2022 a total 104 patients, diagnosed with pituitary adenoma underwent surgery and further followed up in a multidisciplinary team approach in a tertiary care hospital of Kolkata, India. The data obtained were reviewed statistically to satisfy the study objectives. RESULTS: Total 104 operations were done on 98 patients and total cases taken for calculation and analysis was 98, which consist of 11 microadenomas, 81 macroadenomas. Among 35 patients with normal preoperative hormonal assay, one patient developed postoperative hypopituitarism. Among 6 patients with preoperative hypopituitarism 4 patients (66.6%) recovered after surgery. Overall, 85 cases had total disease clearance as detected on post-operative MRI. In functioning pituitary adenoma (FPA) clinical and endocrinological improvement occurred after primary surgery in 85.36% (n = 35) and after revision surgery it was 84.44% (n = 38). Macroadenomas, giant adenomas were found to have statistically significant higher risk of incomplete disease clearance but large adenomas do not have statistically higher risk of incomplete clearance. CONCLUSION: IGNS requires extra time for setup, but with proper registration of tracker instruments it adds precision to the surgery. IGNS supplements endoscopic visualization with localization of target lesion by real time stereotactic feedback using preset preoperative imaging data, thus increasing accuracy, safety and effectiveness of minimally invasive surgery.

Phenolic composition and bioactivity of Ribes magellanicum fruits from southern Patagonia.

Eight Ribes magellanicum collections from three different places in southern Patagonia were compared for content of different groups of phenolics, antioxidant capacity and inhibition of enzymes related to metabolic syndrome (α-amylase, α-glucosidase and pancreatic lipase). The sample with the highest antioxidant capacity was assessed for glutathione (GSH) synthesis stimulation in human gastric adenocarcinoma (AGS) cells. The chemical profile was determined by high performance liquid chromatography with tandem mass spectrometry detection (HPLC-MS/MS) and the main phenolics were quantified. The samples from Navarino Island and Reserva Nacional Magallanes showed higher content of anthocyanins and caffeoylquinic acid, with better activity towards α-glucosidase and antioxidant capacity. A sample from Omora (Navarino Island), significantly increased intracellular GSH content in AGS cells. Some 70 compounds were identified in the fruit extracts by HPLC-MS/MS. The glucoside and rutinoside from delphinidin and cyanidin and 3-caffeoylquinic acid were the main compounds. Different chemical profiles were found according to the collection places.

Identification and characterization of nuclear localization signals in the circumsporozoite protein of Plasmodium falciparum.

Secretory proteins of Plasmodium exhibit differential spatial and functional activity within the host cell nucleus. However, the nuclear localization signals (NLSs) for these proteins remain largely uncharacterized. In this study, we have identified and characterized two NLSs in the circumsporozoite protein of Plasmodium falciparum (Pf-CSP). Both NLSs in the Pf-CSP contain clusters of lysine and arginine residues essential for specific interactions with the conserved tryptophan and asparagine residues of importin-α, facilitating nuclear translocation of Pf-CSP. While the two NLSs of Pf-CSP function independently and are both crucial for nuclear localization, a single NLS of Pf-CSP leads to weak nuclear localization. These findings shed light on the mechanism of nuclear penetrability of secretory proteins of Plasmodium proteins.

The emerging functions of intraflagellar transport 52 in ciliary transport and ciliopathies.

Ciliary transport in eukaryotic cells is an intricate and conserved process involving the coordinated assembly and functioning of a multiprotein intraflagellar transport (IFT) complex. Among the various IFT proteins, intraflagellar transport 52 (IFT52) plays a crucial role in ciliary transport and is implicated in various ciliopathies. IFT52 is a core component of the IFT-B complex that facilitates movement of cargoes along the ciliary axoneme. Stable binding of the IFT-B1 and IFT-B2 subcomplexes by IFT52 in the IFT-B complex regulates recycling of ciliary components and maintenance of ciliary functions such as signal transduction and molecular movement. Mutations in the IFT52 gene can disrupt ciliary trafficking, resulting in dysfunctional cilia and affecting cellular processes in ciliopathies. Such ciliopathies caused by IFT52 mutations exhibit a wide range of clinical features, including skeletal developmental abnormalities, retinal degeneration, respiratory failure and neurological abnormalities in affected individuals. Therefore, IFT52 serves as a promising biomarker for the diagnosis of various ciliopathies, including short-rib thoracic dysplasia 16 with or without polydactyly. Here, we provide an overview of the IFT52-mediated molecular mechanisms underlying ciliary transport and describe the IFT52 mutations that cause different disorders associated with cilia dysfunction.

Assessing type I collagen expression and quality in cellular models of osteogenesis imperfecta.

Osteogenesis imperfecta (OI) is a group of genetic disorders of bone formation characterized by soft and shorter brittle bones in affected individuals. OI is generally considered a collagenopathy resulting from abnormal expression of type I collagen. As assay system to detect the cellular level and quality of type I collagen would help in rapid and correct detection of OI from the diagnostic perspectives. Here, we report an immunofluorescence assay for detection of type I collagen in fibroblast models of OI and represented them into two broad categories based on the expression level and aggregation characteristics of pro-α1(I). Cell phenotypic assays of pro-α1(I) in OI-related gene knocked down fibroblasts revealed aggregates of pro-α1(I) in conditions with knockdown of SERPINF1, CRTAP, P3H1, PPIB, SERPINH1, FKBP10, TMEM38B, MESD, and KDELR2, whereas pro-α1(I) expression was very low in fibroblasts which had knockdown of IFITM5, SP7, BMP1, WNT1, CREB3L1, MBTPS2, and CCDC134. The expression of pro-α1(I) showed abundant and non-aggregated distribution in the fibroblasts with knockdown of non-OI skeletal disorder-related genes (RAB33B and IFT52). The in vitro assay accurately detected abnormally expressed pro-α1(I) levels in cellular models of various types of OI. Thus, this procedure represents a promising point-of-detection assay for potential diagnosis and therapeutic decisions in OI.

Foreign Body Aspiration in Children and Emergency Rigid Bronchoscopy: A Retrospective Observational Study.

Foreign body aspiration is potentially life-threatening in paediatric age group. Early recognition and emergency intervention by Rigid bronchoscopy is life-saving. To highlight various difficulties in emergency paediatric bronchoscopy and discuss our experience in 138 patients. < 12 years children with suspected foreign body aspiration were included. Data of 138 patients < 12 years of age were studied. The most common foreign body found was peanut and organic foreign bodies constituted of total foreign bodies removed. Choking, Cough and sudden onset breathlessness were common symptoms. Tachypnoea, asymmetric breath sound, rhonchi, stridor, reduced chest movements were common signs. Obstructive emphysema was commonest radiological findings. Majority of the patients were discharged within 72 h & only two patients expired. History, clinical and radiological findings are highly indicative of foreign body in the airway. Inspite of being a high risk procedure, Rigid bronchoscopy when performed with necessary expertise,trained anaesthesia team and a paediatric ICU, saves majority of lives of children with tracheobronchial foreign bodies.

Nuclear proteostasis imbalance in laminopathy-associated premature aging diseases.

Laminopathies are a group of rare genetic disorders with heterogeneous clinical phenotypes such as premature aging, cardiomyopathy, lipodystrophy, muscular dystrophy, microcephaly, epilepsy, and so on. The cellular phenomena associated with laminopathy invariably show disruption of nucleoskeleton of lamina due to deregulated expression, localization, function, and interaction of mutant lamin proteins. Impaired spatial and temporal tethering of lamin proteins to the lamina or nucleoplasmic aggregation of lamins are the primary molecular events that can trigger nuclear proteotoxicity by modulating differential protein-protein interactions, sequestering quality control proteins, and initiating a cascade of abnormal post-translational modifications. Clearly, laminopathic cells exhibit moderate to high nuclear proteotoxicity, raising the question of whether an imbalance in nuclear proteostasis is involved in laminopathic diseases, particularly in diseases of early aging such as HGPS and laminopathy-associated premature aging. Here, we review nuclear proteostasis and its deregulation in the context of lamin proteins and laminopathies.

Water-based efficient alkyne transformation towards α-acetoxy/imido-ketones via oxidative coupling reactions using an alkylamine catalyst.

A novel approach is unveiled for the expedited synthesis of valuable α-substituted ketones, utilising aliphatic amine catalysis to drive the oxidative C-O/C-N coupling reaction between alkynes and an appropriate nucleophile. This one-pot synthesis employs hypervalent iodine as both the oxidant and coupling agent. A fast, metal-free, and environmentally benign method is developed for synthesising α-acetoxyketones and α-imidoketones in an aqueous medium. To demonstrate the potential for larger-scale production, a gram-scale reaction is conducted. Moreover, the newly developed methodology has successfully enabled the direct synthesis of cathinone, a psychoactive drug. Overall, this work holds significant promise for the efficient and sustainable synthesis of α-substituted ketones and the potential development of novel biologically active compounds.

CuII-Catalyzed cis-Selective Synthesis of Ketoepoxides from Phenacyl Bromides and Water.

A verity of α,ß-ketoepoxides was synthesized using a CuII-catalyzed oxidative C-C/O-C coupled cyclization strategy with high yield and cis-selectivity. Water is used as the source of oxygen and phenacyl bromide as the carbon in the valuable epoxides. The self-coupling method was extended to cross-coupling between phenacyl bromides with benzyl bromides. A high cis-diastereoselectivity was observed in all the synthesized ketoepoxides. Control experiments and density functional theory (DFT) study were performed to understand the CuII-CuI transition mechanism.

Post-COVID-19 Cardiovascular Sequelae and Myocarditis.

BACKGROUND AND AIM: Post coronavirus disease 2019 (COVID-19) cardiovascular (CV) pathological changes, myocarditis, and myocardial infarctions (MIs) are major public health issues. This review discusses acute and chronic COVID-19 cardiac manifestations. METHODS: The devastating impact of COVID-19 on global healthcare and economies has likely been one of humanity's deadliest calamities in recent decades, as multiple literature and databases were searched from 2020 to 2022. RESULTS: As of April 2022, we identified 73 articles in various electronic databases that discussed the details of COVID-19 and cardiac manifestations. Cardiometabolic risk factors should now, more than ever, be a top priority for clinicians, as their potent role in exacerbating COVID-19 illness severity has been conclusively demonstrated. CONCLUSION: This review discusses cardiac pathology changes, CV consequences of acute COVID-19, microvascular injury and cardiac complications linked with SARS-CoV2, COVID-19 linked with chronic CV disease, therapeutic drug effects on heart used in COVID-19, and possible investigational approaches and management strategies for post-COVID-19 CV consequences. Highlights Cardiac pathology changes: Effect of COVID-19. Mechanism of development of CV consequences in acute COVID-19: Including autopsy studies. Microvascular injury and cardiac complications: Linked with SARS-CoV2. COVID-19 linked with chronic CV disease. Therapeutic drug effects on heart used in COVID-19. Possible investigational approaches and management strategies for post-COVID-19 CV consequences.

Deep intronic mutation in CRTAP results in unstable isoforms of the protein to induce type I collagen aggregation in a lethal type of osteogenesis imperfecta type VII.

Genetic mutations are involved in Mendelian disorders. Unbuffered intronic mutations in gene variants can generate aberrant splice sites in mutant transcripts, resulting in mutant isoforms of proteins with modulated expression, stability, and function in diseased cells. Here, we identify a deep intronic variant, c.794_1403A>G, in CRTAP by genome sequencing of a male fetus with osteogenesis imperfecta (OI) type VII. The mutation introduces cryptic splice sites in intron-3 of CRTAP, resulting in two mature mutant transcripts with cryptic exons. While transcript-1 translates to a truncated isoform (277 amino acids) with thirteen C-terminal non-wild-type amino acids, transcript-2 translates to a wild-type protein sequence, except that this isoform contains an in-frame fusion of non-wild-type twenty-five amino acids in a tetratricopeptide repeat sequence. Both mutant isoforms of CRTAP are unstable due to the presence of a unique 'GWxxI' degron, which finally leads to loss of proline hydroxylation and aggregation of type I collagen. Although type I collagen aggregates undergo autophagy, the overall proteotoxicity resulted in death of the proband cells by senescence. In summary, we present a genetic disease pathomechanism by linking a novel deep intronic mutation in CRTAP to unstable mutant isoforms of the protein in lethal OI type VII.

Cu(I)-catalysed cross-coupling reaction of in situ generated azomethine ylides towards easy construction of fused N-heterocycles.

In this study, we have devised a new method for synthesizing highly valuable 5,6,7,8a-tetrahydropyrrolo[2,1-b]thiazoles using a decarboxylative C-N coupling reaction between phenyl glyoxal and proline or its analogue, which is catalyzed by CuI in the presence of K2CO3. This reaction is followed by a regiospecific C-C and C-S coupling cyclization with dialkyl trithiocarbonate. Furthermore, we have demonstrated that this cross-coupling method can also be extended to imines, leading to the formation of fused symmetrical and unsymmetrical 6,7-dihydro-5H-pyrrolo[1,2-a]imidazoles. This finding greatly expands the scope and versatility of the synthetic approach. Therefore, this work represents a significant contribution to the field of organic synthesis, providing a novel and efficient method for the preparation of fused N-heterocyclic compounds that could have useful applications in areas such as material science and pharmaceuticals.

Mutant MESD links cellular stress to type I collagen aggregation in osteogenesis imperfecta type XX.

Aberrant forms of endoplasmic reticulum (ER)-resident chaperones are implicated in loss of protein quality control in rare diseases. Here we report a novel mutation (p.Asp233Asn) in the ER retention signal of MESD by whole exome sequencing of an individual diagnosed with osteogenesis imperfecta (OI) type XX. While MESDD233N has similar stability and chaperone activity as wild-type MESD, its mislocalization to cytoplasm leads to imbalance of ER proteostasis, resulting in improper folding and aggregation of proteins, including LRP5 and type I collagen. Aggregated LRP5 loses its plasma membrane localization to disrupt the expression of WNT-responsive genes, such as BMP2, BMP4, in proband fibroblasts. We show that MESD is a direct chaperone of pro-α1(I) [COL1A1], and absence of MESDD233N in ER results in cytosolic type I collagen aggregates that remain mostly not secreted. While cytosolic type I collagen aggregates block the intercellular nanotubes, decreased extracellular type I collagen also results in loss of interaction of ITGB1 with type I collagen and weaker attachment of fibroblasts to matrix. Although proband fibroblasts show increased autophagy to degrade the aggregated type I collagen, an overall cellular stress overwhelms the proband fibroblasts. In summary, we present an essential chaperone function of MESD for LRP5 and type I collagen and demonstrating how the D233N mutation in MESD correlates with impaired WNT signaling and proteostasis in OI.

Genome sequencing identifies a large non-coding region deletion of SNX10 causing autosomal recessive osteopetrosis.

Autosomal recessive osteopetrosis (ARO) is a rare genetic disorder caused by impaired osteoclast activity. In this study, we describe a 4-year-old boy with increased bone density due to osteopetrosis, autosomal recessive 8. Using genome sequencing, we identified a large deletion in the 5'-untranslated region (UTR) of SNX10 (sorting nexin 10), where the regulatory region of this gene is located. This large deletion resulted in the absence of the SNX10 transcript and led to abnormal osteoclast activity. SNX10 is one of the nine genes known to cause ARO, shown to interact with V-ATPase (vacuolar type H( + )-ATPase), as it plays an important role in bone resorption. Our study highlights the importance of regulatory regions in the 5'-UTR of SNX10 for its expression while also demonstrating the importance of genome sequencing for detecting large deletion of the regulatory region of SNX10.

Acyl-CoA binding protein regulates nutrient-dependent autophagy.

BACKGROUND: Homeostasis of autophagy under normal conditions and nutrient stress is maintained by adaptive activation of regulatory proteins. However, the protein-lipid crosstalk that modulates the switch from suppression to activation of autophagy initiation is largely unknown. RESULTS: Here, we show that human diazepam-binding inhibitor (DBI), also known as acyl-CoA binding protein (ACBP), binds to phosphatidylethanolamine of the phagophore membrane under nutrient-rich growth conditions, leading to inhibition of LC3 lipidation and suppression of autophagy initiation. Specific residues, including the conserved tyrosine residues of DBI, interact with phosphatidylethanolamine to stabilize the later molecule in the acyl-CoA binding cavity of the protein. Under starvation, phosphorylation of serine-21 of DBI mediated by the AMP-activated protein kinase results in a drastic reduction in the affinity of the protein for phosphatidylethanolamine. The release of serine-21 phosphorylated DBI from the phagophore upon nutrient starvation restores the high LC3 lipidation flux and maturation of the phagophore to autophagosome. CONCLUSION: DBI acts as a strategic barrier against overactivation of phagophore maturation under nutrient-rich conditions, while triggering autophagy under nutrient-deficient conditions.

Fundoplication in laparoscopic Heller's cardiomyotomy for achalasia.

BACKGROUND: Laparoscopic Heller's cardiomyotomy (LHC) is the preferred treatment of achalasia. It improves dysphagia by dividing muscles of the lower oesophageal sphincter, but this intervention can result in debilitating gastro-oesophageal reflux symptoms in some patients. To prevent these reflux symptoms, most surgeons add a fundoplication to Heller's cardiomyotomy, but there is no consensus regarding this or the type of fundoplication which is best suited for the purpose. OBJECTIVES: To assess how the addition of a fundoplication affects postoperative reflux and dysphagia in people undergoing LHC and compare the different types of fundoplications used in combination with LHC to determine which is better at controlling reflux without worsening the dysphagia. SEARCH METHODS: We searched three databases (CENTRAL, MEDLINE and Embase) on 31 October 2021 and trial registers to identify all published and unpublished randomised controlled trials (RCTs) in any language, comparing different fundoplications used in combination with LHC to treat achalasia. We also included RCTs where LHC with a fundoplication is compared with LHC without any fundoplication. SELECTION CRITERIA: We only included RCTs which recruited adult participants with achalasia undergoing LHC with minimal hiatal dissection. We excluded non-randomised studies or studies involving paediatric participants. We also excluded studies where the procedure was done by open surgery and where circumferential hiatal dissection of the oesophagus was carried out, unless it was necessary to reduce a hiatus hernia or to facilitate a Toupet or Nissen fundoplication. DATA COLLECTION AND ANALYSIS: Two review authors independently identified studies to be included, assessed risk of bias using the Cochrane RoB 1 tool, and extracted the data. We calculated the risk ratio (RR) with 95% confidence interval (CI) using both fixed-effect and random-effect models with Review Manager (RevMan) software. MAIN RESULTS: We included eight studies in this review, with a total of 571 participants with an average age of 45 years (range 33.5 to 50). LHC without any fundoplication was performed in 65 (11.3%) participants, 298 (52.1%) had Dor fundoplication, 81 (14.1%) had Toupet fundoplication, 72 (12.6%) had Nissen's fundoplication, and 55 (9.6%) participants had angle of His accentuation. Three studies with a total of 143 participants compared LHC + Dor to LHC without fundoplication. We found that the evidence is very uncertain as to whether the addition of a Dor fundoplication made any difference to the outcome of postoperative pathological acid reflux (RR 0.37, 95% CI 0.07 to 1.89; I2 = 56%; 2 studies, 97 participants; very low-certainty evidence) and uncertain for severe postoperative dysphagia (RR 3.00, 95% CI 0.34 to 26.33; I2 = 0%; 3 studies, 142 participants; low-certainty evidence). Three studies with 174 participants compared LHC + Dor to LHC + Toupet. The evidence suggests that there may be little to no difference in the outcomes of postoperative pathological acid reflux (RR 0.75, 95% CI 0.23 to 2.43; I2 = 60%; 3 studies, 105 participants; low-certainty evidence) and severe postoperative dysphagia (RR 0.78, 95% CI 0.19 to 3.15; I2 = 0%; 3 studies, 123 participants; low-certainty evidence) between the two interventions, but the certainty of the evidence is low. One study with 138 participants compared LHC + Dor to LHC + Nissen. Nissen fundoplication caused increased severe postoperative dysphagia (RR 0.19, 95% CI 0.04 to 0.83; 1 study, 138 participants; high-certainty evidence) when compared to Dor fundoplication. This study did not show a difference in postoperative pathological acid reflux (RR 4.72, 95% CI 0.23 to 96.59; 1 study, 138 participants; low-certainty evidence), but the certainty of evidence is low. One study with 110 participants compared LHC + Dor with LCH + angle of His accentuation, and reported that severe postoperative dysphagia was similar between the two interventions (RR 1.56, 95% CI 0.27 to 8.95; 1 study, 110 participants; moderate-certainty evidence), with moderate certainty of evidence. This study did not report on postoperative pathological acid reflux. AUTHORS' CONCLUSIONS: When LHC was performed with minimal hiatal dissection, we were very uncertain whether the addition of a Dor fundoplication made a difference in controlling postoperative reflux, and we were uncertain if it increased the risk of severe postoperative dysphagia. There may be little to no difference in the outcomes of postoperative pathological acid reflux or severe dysphagia between Dor and Toupet fundoplications when used in combination with LHC, but the certainty of the evidence is low. Nissen (total) fundoplication used in combination with LHC for achalasia increased the risk of severe postoperative dysphagia. The angle of His accentuation and Dor fundoplication had a similar effect on severe postoperative dysphagia when combined with LHC, but their effect on postoperative pathological acid reflux was not reported.

The E262K mutation in Lamin A links nuclear proteostasis imbalance to laminopathy-associated premature aging.

Deleterious, mostly de novo, mutations in the lamin A (LMNA) gene cause spatio-functional nuclear abnormalities that result in several laminopathy-associated progeroid conditions. In this study, exome sequencing in a sixteen-year-old male with manifestations of premature aging led to the identification of a mutation, c.784G>A, in LMNA, resulting in a missense protein variant, p.Glu262Lys (E262K), that aggregates in nucleoplasm. While bioinformatic analyses reveal the instability and pathogenicity of LMNAE262K , local unfolding of the mutation-harboring helical region drives the structural collapse of LMNAE262K into aggregates. The E262K mutation also disrupts SUMOylation of lysine residues by preventing UBE2I binding to LMNAE262K , thereby reducing LMNAE262K degradation, aggregated LMNAE262K sequesters nuclear chaperones, proteasomal proteins, and DNA repair proteins. Consequently, aggregates of LMNAE262K disrupt nuclear proteostasis and DNA repair response. Thus, we report a structure-function association of mutant LMNAE262K with toxicity, which is consistent with the concept that loss of nuclear proteostasis causes early aging in laminopathies.

Silver nanoparticle synthesis and their potency against multidrug-resistant bacteria: a green approach from tissue-cultured Coleus forskohlii.

Drug resistance is a major concern nowadays, and finding alternatives of the well-known antibiotic is necessary. Green nanoparticles are emerging as a tenable alternative to this with a large spectrum of activity. The present manuscript describes an eco-friendly approach for green synthesis of silver nanoparticles from both in vitro and in vivo leaf extract of Coleus forskohlii. Leaf extracts were used in synthesis of nanoparticles which were further analyzed through UV-Vis, dynamic light scattering, energy-dispersive spectroscopy, and transmission electron microscopy. Antimicrobial activity of silver nanoparticles alone, as well as crude extract of the plant itself, was carried out against eight multidrug-resistant respiratory tract infecting pathogenic strains. Satisfactory antimicrobial activities were found with nanoparticles, in vitro and in vivo leaf extracts. However, gradually higher to lower inhibition potential against pathogenic bacterial strains was found in silver nanoparticles, in vitro and in vivo leaf extracts. Seven bioactive compounds were detected in the crude extract through gas chromatography-mass spectroscopy analysis. Results revealed that nanoparticle formation occurred in a wide range of sizes (10-50 nm) and shapes (trigonal, hexagonal, spherical, rod). The diversity in size and shape of the nanoparticles makes them biologically active. Silver nanoparticle exhibits significantly better antimicrobial activities as compared to the plant extract in case of nearly all pathogens with a maximum zone of inhibition of 15.33 ± 0.94 mm where more than 12 well-known antibiotics failed to respond. Because of this broad-spectrum activity of nanoparticles as well as the leaf extracts against life-threatening microbes, it can be used as future generation drugs.

HYPK coordinates degradation of polyneddylated proteins by autophagy.

Selective degradation of protein aggregates by macroautophagy/autophagy is an essential homeostatic process of safeguarding cells from the effects of proteotoxicity. Among the ubiquitin-like proteins, NEDD8 conjugation to misfolded proteins is prominent in stress-induced protein aggregates, albeit the function of neddylation in autophagy is unclear. Here, we report that polyneddylation functions as a post-translational modification for autophagic degradation of proteotoxic-stress induced protein aggregates. We also show that HYPK functions as an autophagy receptor in the polyneddylation-dependent aggrephagy. The scaffolding function of HYPK is facilitated by its C-terminal ubiquitin-associated domain and N-terminal tyrosine-type LC3-interacting region which bind to NEDD8 and LC3 respectively. Both NEDD8 and HYPK are positive modulators of basal and proteotoxicity-induced autophagy, leading to protection of cells from protein aggregates, such as aggregates of mutant HTT exon 1. Thus, we propose an indispensable and additive role of neddylation and HYPK in clearance of protein aggregates by autophagy, resulting in cytoprotective effect during proteotoxic stress.Abbreviations: ATG5, autophagy related 5; ATG12, autophagy related 12; ATG14, autophagy related 14; BECN1, beclin 1; CBL, casitas B-lineage lymphoma; CBLB, Cbl proto-oncogene B; GABARAP, GABA type A receptor-associated protein; GABARAPL1, GABA type A receptor associated protein like 1; GABARAPL2, GABA type A receptor associated protein like 2; GFP, green fluorescent protein; HTT, huntingtin; HTT97Q exon 1, huntingtin 97-glutamine exon 1; HUWE1, HECT, UBA and WWE domain containing E3 ubiquitin protein ligase 1; HYPK, huntingtin interacting protein K; IgG, immunoglobulin G; IMR-32, Institute for Medical Research-32; KD, knockdown; Kd, dissociation constant; LAMP1, lysosomal associated membrane protein 1; LIR, LC3 interacting region; MAP1LC3/LC3, microtubule associated protein 1 light chain 3; MAP1LC3A/LC3A, microtubule associated protein 1 light chain 3 alpha; MAP1LC3B/LC3B, microtubule associated protein 1 light chain 3 beta; MARK1, microtubule affinity regulating kinase 1; MARK2, microtubule affinity regulating kinase 2; MARK3, microtubule affinity regulating kinase 3; MARK4, microtubule affinity regulating kinase 4; MCF7, Michigan Cancer Foundation-7; MTOR, mechanistic target of rapamycin kinase; NAE1, NEDD8 activating enzyme E1 subunit 1; NBR1, NBR1 autophagy cargo receptor; NEDD8, NEDD8 ubiquitin like modifier; Ni-NTA, nickel-nitrilotriacetic acid; NUB1, negative regulator of ubiquitin like proteins 1; PIK3C3, phosphatidylinositol 3-kinase catalytic subunit type 3; PolyQ, poly-glutamine; PSMD8, proteasome 26S subunit, non-ATPase 8; RAD23A, RAD23 homolog A, nucleotide excision repair protein; RAD23B, RAD23 homolog B, nucleotide excision repair protein; RFP, red fluorescent protein; RPS27A, ribosomal protein S27a; RSC1A1, regulator of solute carriers 1; SNCA, synuclein alpha; SIK1, salt inducible kinase 1; siRNA, small interfering ribonucleic acid; SOD1, superoxide dismutase 1; SPR, surface plasmon resonance; SQSTM1, sequestosome 1; SUMO1, small ubiquitin like modifier 1; TAX1BP1, Tax1 binding protein 1; TDRD3, tudor domain containing 3; TNRC6C, trinucleotide repeat containing adaptor 6C; TOLLIP, toll interacting protein; TUBA, tubulin alpha; TUBB, tubulin beta class I; UBA, ubiquitin-associated; UBA1, ubiquitin like modifier activating enzyme 1; UBA5, ubiquitin like modifier activating enzyme 5; UBAC1, UBA domain containing 1; UBAC2, UBA domain containing 2; UBAP1, ubiquitin associated protein 1; UBAP2, ubiquitin associated protein 2; UBASH3B, ubiquitin associated and SH3 domain containing B; UBD/FAT10, ubiquitin D; UBE2K, ubiquitin conjugating enzyme E2 K; UBLs, ubiquitin-like proteins; UBL7, ubiquitin like 7; UBQLN1, ubiquilin 1; UBQLN2, ubiquilin 2; UBQLN3, ubiquilin 3; UBQLN4, ubiquilin 4; UBXN1, UBX domain protein 1; ULK1, unc-51 like autophagy activating kinase 1; URM1, ubiquitin related modifier 1; USP5, ubiquitin specific peptidase 5; USP13, ubiquitin specific peptidase 13; VPS13D, vacuolar protein sorting 13 homolog D.