Effects of treatment processes on AOC removal and changes of bacterial diversity in a water treatment plant.

The effectiveness of different treatment processes on assimilable organic carbon (AOC) removal and bacterial diversity variations was evaluated in a water treatment plant. The van der Kooij technique was applied for AOC analysis and responses of bacterial communities were characterized by the metagenomics assay. Results show that the AOC concentrations were about 93, 148, 43, 51, 37, and 38 µg acetate-C/L in effluents of raw water basin, preozonation, rapid sand filtration (RSF), ozonation, biofiltration [biological activated carbon (BAC) filtration], and chlorination (clear water), respectively. Increased AOC concentrations were observed after preozonation, ozonation, and chlorination units due to the production of biodegradable organic matters after the oxidation processes. Results indicate that the oxidation processes were the main causes of AOC formation, which resulted in significant increases in AOC concentrations (18-59% increment). The AOC removal efficiencies were 47, 28, and 60% in the RSF, biofiltration, and the whole system, respectively. RSF and biofiltration were responsible for the AOC treatment and both processes played key roles in AOC removal. Thus, both RSF and biofiltration processes would contribute to AOC treatment after oxidation. Sediments from the raw water basin and filter samples from RSF and BAC units were collected and analyzed for bacterial communities. Results from scanning electron microscope analysis indicate that bacterial colonization was observed in filter materials. This indicates that the surfaces of the filter materials were beneficial to bacterial growth and AOC removal via the adsorption and biodegradation mechanisms. Next generation sequencing analyses demonstrate that water treatment processes resulted in the changes of bacterial diversity and community profiles in filters of RSF and BAC. According to the findings of bacterial composition and interactions, the dominant bacterial phyla were Proteobacteria (41% in RSF and 56% in BAC) followed by Planctomycetes and Acidobacteria in RSF and BAC systems, which might affect the AOC biodegradation efficiency. Results would be useful in developing AOC treatment and management processes in water treatment plants.

Suppression of Host Innate Immune Response by Hepatitis C Virus via Induction of Autophagic Degradation of TRAF6.

Tumor necrosis factor receptor (TNFR)-associated factor 6 (TRAF6) is an important adaptor molecule that mediates the TNFR family and interleukin-1 (IL-1)/Toll-like receptor (TLR) signaling cascades. These pathways are important for the host to control viral infections. In this report, we demonstrated that hepatitis C virus (HCV) depleted TRAF6 from its host cells through a posttranslational mechanism. This depletion was independent of proteasomes, as it was not affected by the proteasome inhibitor MG132, but it was suppressed by bafilomycin A1, which led to the association of TRAF6 with autophagosomes. As bafilomycin A1 is a vacuolar ATPase inhibitor that inhibits autophagic protein degradation, these results suggested that HCV depleted TRAF6 via autophagy. The degradation of TRAF6 was apparently mediated by the p62 sequestosome protein, which is a factor important for selective autophagy, as it could bind to TRAF6 and its silencing stabilized TRAF6. The depletion of TRAF6 suppressed activation of NF-κB and induction of proinflammatory cytokines and enhanced HCV replication. In contrast, the overexpression of TRAF6 suppressed HCV replication. These results revealed a novel mechanism that was used by HCV to disrupt the host innate immune responses for viral replication and persistence. IMPORTANCE: HCV can cause severe liver diseases and is one of the most important human pathogens. It establishes chronic infections in the great majority of patients that it infects, indicating that it has evolved sophisticated mechanisms to evade host immunity. TRAF6 is an important signaling molecule that mediates activation of NF-κB and expression of proinflammatory cytokines and interferons. In this study, we found that HCV infection suppressed the host innate immune response through the induction of autophagic degradation of TRAF6. This finding provided important information for further understanding how HCV evades host immunity to establish persistence.

Lack of autophagy induces steroid-resistant airway inflammation.

BACKGROUND: Neutrophilic corticosteroid-resistant asthma accounts for a significant proportion of asthma; however, little is known about the mechanisms that underlie the pathogenesis of the disease. OBJECTIVE: We sought to address the role of autophagy in lung inflammation and the pathogenesis of corticosteroid-resistant neutrophilic asthma. METHODS: We developed CD11c-specific autophagy-related gene 5 (Atg5)(-/-) mice and used several murine models to investigate the role of autophagy in asthmatic patients. RESULTS: For the first time, we found that deletion of the Atg5 gene specifically in CD11c(+) cells, which leads to impairment of the autophagy pathway, causes unprovoked spontaneous airway hyperreactivity and severe neutrophilic lung inflammation in mice. We found that severe lung inflammation impairs the autophagy pathway, particularly in pulmonary CD11c(+) cells in wild-type mice. We further found that adoptive transfer of Atg5(-/-), but not wild-type, bone marrow-derived dendritic cells augments lung inflammation with increased IL-17A levels in the lungs. Our data indicate that neutrophilic asthma in Atg5(-/-) mice is glucocorticoid resistant and IL-17A dependent. CONCLUSION: Our results suggest that lack of autophagy in pulmonary CD11c(+) cells induces neutrophilic airway inflammation and hyperreactivity.

Technical standards for hepatitis B virus X protein (HBx) research.

Chronic infection with hepatitis B virus (HBV) is a risk factor for developing hepatocellular carcinoma (HCC). The life cycle of HBV is complex and has been difficult to study because HBV does not infect cultured cells. The HBV regulatory X protein (HBx) controls the level of HBV replication and possesses an HCC cofactor role. Attempts to understand the mechanism(s) that underlie HBx effects on HBV replication and HBV-associated carcinogenesis have led to many reported HBx activities that are likely influenced by the assays used. This review summarizes experimental systems commonly used to study HBx functions, describes limitations of these experimental systems that should be considered, and suggests approaches for ensuring the biological relevance of HBx studies.

HCV-induced autophagy and innate immunity.

The interplay between autophagy and host innate immunity has been of great interest. Hepatitis C virus (HCV) impedes signaling pathways initiated by pattern-recognition receptors (PRRs) that recognize pathogens-associated molecular patterns (PAMPs). Autophagy, a cellular catabolic process, delivers damaged organelles and protein aggregates to lysosomes for degradation and recycling. Autophagy is also an innate immune response of cells to trap pathogens in membrane vesicles for removal. However, HCV controls the autophagic pathway and uses autophagic membranes to enhance its replication. Mitophagy, a selective autophagy targeting mitochondria, alters the dynamics and metabolism of mitochondria, which play important roles in host antiviral responses. HCV also alters mitochondrial dynamics and promotes mitophagy to prevent premature cell death and attenuate the interferon (IFN) response. In addition, the dysregulation of the inflammasomal response by HCV leads to IFN resistance and immune tolerance. These immune evasion properties of HCV allow HCV to successfully replicate and persist in its host cells. In this article, we discuss HCV-induced autophagy/mitophagy and its associated immunological responses and provide a review of our current understanding of how these processes are regulated in HCV-infected cells.

Krüppel-like factor 15 activates hepatitis B virus gene expression and replication.

UNLABELLED: Hepatitis B virus (HBV) is a small DNA virus that requires cellular transcription factors for the expression of its genes. To understand the molecular mechanisms that regulate HBV gene expression, we conducted a yeast one-hybrid screen to identify novel cellular transcription factors that may control HBV gene expression. Here, we demonstrate that Krüppel-like factor 15 (KLF15), a liver-enriched transcription factor, can robustly activate HBV surface and core promoters. Mutations in the putative KLF15 binding site in the HBV core promoter abolished the ability of KLF15 to activate the core promoter in luciferase assays. Furthermore, the overexpression of KLF15 stimulated the expression of HBV surface antigen (HBsAg) and the core protein and enhanced viral replication. Conversely, small interfering RNA knockdown of the endogenous KLF15 in Huh7 cells resulted in a reduction in HBV surface- and core-promoter activities. In electrophoretic mobility shift and chromatin immunoprecipitation assays, KLF15 binds to DNA probes derived from the core promoter and the surface promoter. Introduction of an expression vector for KLF15 short hairpin RNA, together with the HBV genome into the mouse liver using hydrodynamic injection, resulted in a significant reduction in viral gene expression and DNA replication. Additionally, mutations in the KLF15 response element in the HBV core promoter significantly reduced viral DNA levels in the mouse serum. CONCLUSION: KLF15 is a novel transcriptional activator for HBV core and surface promoters. It is possible that KLF15 may serve as a potential therapeutic target to reduce HBV gene expression and viral replication.

Targeting of the hepatitis B virus precore protein to the endoplasmic reticulum membrane: after signal peptide cleavage translocation can be aborted and the product released into the cytoplasm.

The major hepatitis B virus (HBV) core protein is a viral structural protein involved in nucleic acid binding. Its coding sequence contains an extension of 29 codons (the "precore" region) at the amino terminus of the protein which is present in a fraction of the viral transcripts. This region is evolutionarily conserved among mammalian and avian HBVs, suggesting it has functional importance, although at least for duck HBV it has been shown to be nonessential for replication of infectious virions. Using in vitro assays for protein translocation across the endoplasmic reticulum membrane, we found that the precore region of the HBV genome encodes a signal sequence. This signal sequence was recognized by signal recognition particle, which targeted the nascent precore protein to the endoplasmic reticulum membrane with efficiencies comparable to those of other mammalian secretory proteins. A 19-amino acid signal peptide was removed by signal peptidase on the lumenal side of the microsomal membrane, generating a protein similar to the HBV major core protein, but containing 10 additional amino acids from the precore region at its amino terminus. Surprisingly, we found that 70-80% of this signal peptidase-cleaved product was localized on the cytoplasmic side of the microsomal vesicles and was not associated with the membranes. We conclude that translocation was aborted by an unknown mechanism, then the protein disengaged from the translocation machinery and was released back into the cytoplasm. Thus, a cytoplasmically disposed protein was created whose amino terminus resulted from signal peptidase cleavage. The remaining 20-30% appeared to be completely translocated into the lumen of the microsomes. A deletion mutant lacking the carboxy-terminal nucleic acid binding domain of the precore protein was similarly partitioned between the lumen of the microsomes and the cytoplasmic compartment, indicating that this highly charged domain is not responsible for the aborted translocation. We discuss the implications of our findings for the protein translocation process and suggest a possible role in the virus life cycle.

Source identification and ecological impact evaluation of PAHs in urban river sediments: A case study in Taiwan.

The Love River and Ho-Jin River, two major urban rivers in Kaohsiung City, Taiwan, are moderately to heavily polluted because different types of improperly treated wastewaters are discharged into the rivers. In this study, sediment and river water samples were collected from two rivers to investigate the river water quality and accumulation of polycyclic aromatic hydrocarbons (PAHs) in sediments. The spatial distribution, composition, and source appointment of PAHs of the sediments were examined. The impacts of PAHs on ecological system were assessed using toxic equivalence quotient (TEQ) of potentially carcinogenic PAHs (TEQcarc) and sediment quality guidelines. The average PAHs concentrations ranged from 2161 ng/g in Love River sediment to 160 ng/g in Ho-Jin River sediment. This could be due to the fact that Love River Basin had much higher population density and pyrolytic activities. High-ring PAHs (4-6 rings) contributed to 59-90% of the total PAHs concentrations. Benzo(a)pyrene (BaP) had the highest toxic equivalence quotient (up to 188 ng TEQ/g). Moreover, the downstream sediments contained higher TEQ of total TPHs than midstream and upstream sediment samples. The PAHs were adsorbed onto the fine particles with high organic content. Results from diagnostic ratio analyses indicate that the PAHs in two urban river sediments might originate from oil/coal combustion, traffic-related emissions, and waste combustion (pyrogenic activities). Future pollution prevention and management should target the various industries, incinerators, and transportation emission in this region to reduce the PAHs pollution.

Hepatocyte-specific expression of the hepatitis B virus core promoter depends on both positive and negative regulation.

The core promoter of hepatitis B virus shows hepatocyte specificity, which is largely dependent on an upstream regulatory sequence that overlaps with viral enhancer II. Footprint analyses by numerous groups have shown binding by cellular proteins over a large stretch of DNA in this region, but the identity of these proteins and their role in core promoter function remain largely unknown. We present data showing that the transcription factor HNF-4 is one such factor, as it activates the core promoter approximately 20-fold via a binding site within the upstream regulatory sequence. Since HNF-4 is enriched in hepatocytes, its involvement at least partially explains the hepatocyte specificity of this promoter. In addition, however, we have found a region upstream of the HNF-4 site that suppresses activation by HNF-4 in HeLa cells but not in hepatoma cells. Therefore, the cell type specificity of the core promoter appears to result from a combination of activation by one or more factors specifically enriched in hepatocytes and repression by some other factor(s) present in nonhepatocytes, and it may provide a convenient model system for studying this type of tissue-specific transcriptional regulation in mammalian cells.

The 5'-terminal sequences of the genomic RNAs of several alphaviruses.

The 5'-terminal sequences of the genomic RNAs of several alphaviruses have been determined. The nucleotide sequences at the extreme 5' termini are not highly conserved among the alphaviruses, but a similar stem and loop structure, which begins at the 5' end and utilizes about the first 40 nucleotides, can be formed in each case. Downstream from this structure, beginning about 150 nucleotides from the 5' end, a conserved sequence of 51 nucleotides is found which can form two stable hairpin structures. Examination of the 5'-terminal and 3'-terminal sequences suggests that part of this conserved nucleotide sequence may be involved in cyclization of the RNA. A model is proposed for the function of the 5'-terminal sequences in RNA replication. In addition, sequence homologies among these RNAs strongly support the hypothesis that an AUG codon, which occurs at 60 to 80 nucleotides from the 5' end, depending on the virus, and which may or may not be the first AUG codon, is used for initiation of translation of the non-structural proteins and allows a comparison of the deduced amino acid sequences in the NH2-terminal regions.

Autophagy inhibits oxidative stress and tumor suppressors to exert its dual effect on hepatocarcinogenesis.

The role of autophagy in carcinogenesis is controversial and apparently complex. By using mice with hepatocyte-specific knockout of Atg5, a gene essential for autophagy, we longitudinally studied the role of autophagy in hepatocarcinogenesis. We found that impairing autophagy in hepatocytes would induce oxidative stress and DNA damage, followed by the initiation of hepatocarcinogenesis, which could be suppressed by the antioxidant N-acetylcysteine. Interestingly, these mice developed only benign tumors with no hepatocellular carcinoma (HCC), even after the treatment with diethylnitrosamine, which induced HCC in wild-type mice. The inability of mice to develop HCC when autophagy was impaired was associated with the induction of multiple tumor suppressors including p53. Further analysis indicated that the induction of p53 was associated with the DNA-damage response. Tumorigenesis studies using an established liver tumor cell line confirmed a positive role of autophagy in tumorigenesis and a negative role of p53 in this process when autophagy was impaired. Our studies thus demonstrate that autophagy is required to maintain healthy mitochondria and to reduce oxidative stress and DNA damage to prevent the initiation of hepatocarcinogenesis. However, once hepatocarcinogenesis has been initiated, its presence is also required to suppress the expression of tumor suppressors to promote the development of HCC.

Detection of Cellular Proteins and Viral Core Protein Interacting with the 5' Untranslated Region of Hepatitis C Virus RNA.

Hepatitis C virus (HCV) is a pesti- and flavi-like virus, which contains a highly conserved 5'-untranslated region (UTR). This region is implicated in the regulation of both translation and RNA replication. To examine the possible cellular factors involved in HCV replication, we performed UV cross-linking experiments to detect cellular protein binding to 5'-UTR of HCV RNA. No cytoplasmic proteins were found to cross-link to 5'-UTR. Surprisingly, when nuclear extracts were used for UV cross-linking, a major protein of 110 kD and several other minor proteins were detected. Competition assays confirmed that the binding of the 110-kD protein was specific to the 5'-UTR. The protein-binding site was mapped within the 78-nt region between nucleotides 199 and 277 from the 5' end of the viral RNA. This protein was present in several different cell lines tested. No cellular proteins specifically bound to the complementary strands of the 5'-UTR. We have also shown by an RNA-protein blotting assay that 5'-UTR bound to the HCV core protein, which can be translocated to the nuclei. These findings suggest that HCV RNA may enter nuclei by complexing with the viral core protein and interact with nuclear proteins that are involved in the regulation of RNA replication or translation. It is thus possible that HCV employs a replication strategy distinct from its related pestiviruses or flaviviruses. Copyright 1995 S. Karger AG, Basel

Expression and Dimerization of Hepatitis C Virus Core Protein in E. coli.

Hepatitis C virus (HCV) is a positive-stranded RNA virus with a genome size of about 9-10 kb. The genome of this virus encodes a polyprotein with a length of over 3000 amino acids. This polyprotein is cleaved by cellular and viral proteases to generate at least 10 viral gene products. Recent reports have indicated that there are extensive interactions between various HCV proteins: the core (capsid) protein can interact with itself (1) and with the El envelope protein (2); El protein can interact with the E2 envelope protein (3,4) which in turn can be covalently linked to its following p7 protein and interact with another integral membrane protein named NS2 (5); NS2 can also interact with NS5A and NS5B nonstructural proteins (6); and NS3 proteinase/helicase has also been shown to complex with the NS4A protein (6,7). Thus, most of the known HCV proteins interact with at least another HCV protein. These interactions are presumably very important for morphogenesis and replication of HCV.

Transoral anterior decompression and fusion of chronic irreducible atlantoaxial dislocation with spinal cord compression.

STUDY DESIGN: In this study, 10 patients with chronic irreducible atlantoaxial dislocation were treated by transoral anterior decompression and fusion. OBJECTIVES: To examine the benefits of the transoral approach, the patients treated with this procedure were compared with the historical control subjects after 2 years of follow-up. SUMMARY AND BACKGROUND DATA: Chronic irreducible atlantoaxial dislocation with cord compression is difficult to treat because the cord is compressed posteriorly by the posterior arch of the atlas as well as anteriorly by the posterior-superior portion of the axial body and nonunited dens. Its irreducibility, as a result of the bony scarring between the dens and the anterior body of the axis, and the locking of the lateral joints of C1-C2, makes reduction more complex. Posterior surgical approaches have been associated with high morbidity and mortality. METHODS: Ten patients were diagnosed and followed up by clinical symptoms, radiography, pantopaque myelography, and computed tomography. They were treated surgically by transoral decompression and fusion. During the surgery the nonunited dens as well as callus, granulation, and scar tissue were removed; the cartilage of the articular surfaces of the atlantoaxial joint was excised. Postoperative treatment included skull-cervical biaxial traction, tracheostomy care, nasal feeding, and Minerva cast. RESULTS: The 2- to 6-year follow-up showed that four out of 10 patients recovered completely and returned to work, three recovered to a great degree and ambulated, two partially recovered, and one recovered poorly. CONCLUSION: Transoral decompression and fusion offered satisfactory results in a series of patients with chronic irreducible atlantoaxial dislocation. None of the patients showed serious complications of stability, even though only one had a secondary posterior fusion. Therefore, anterior decompression associated with subtotal obliteration of the atlantoaxial joints without bone grafts is a feasible therapy for irreducible atlantoaxial dislocation using a multifunctional bed and biaxial traction.

[Medium-chain triglycerides metabolism and its application in total parenteral nutrition].

Twenty patients undergoing uneventful gastrectomy were randomly assigned to receive TPN containing either 10% Intralipid or 10% Lipofundin (MCT/LCT) beginning postoperative day (POD) 1 through POD 6. Patients were given non-protein energy 27 kcal/kg/d and nitrogen 0.14 g/kg/d through peripheral vein along with fat emulsion. Body weight, hemoglobin, blood lymphocyte count, SGPT, serum bilirubin, AKP, BUN, Cr, serum albumin, transferrin, prealbumin, fibronectin, creatine phosphokinase, serum and plasma cholesterol, triglycerides, plasma free fatty acids, blood sugar, serum insulin, urinary creatinine and nitrogen balance were monitored. It was found that MCT-based fat emulsion was tolerated without any side effects. Kinetics study showed that levels of medium chain free fatty acids increased during MCT-based fat emulsion infusion, but returned to normal within 2 hours on cessation of infusion, indicating good clearance of MCT. Plasma concentration of triglycerides in the LCT group was higher than that in the MCT group at 2 hours after infusion. On POD 6, better nitrogen balance was observed in the MCT group, 0.44 +/- 0.21 g/d (-1.4 +/- 0.51 g/d in the LCT group). Urinary excretion of creatinine in the MCT group was also less than in the LCT group (0.76 +/- 0.03 g/d vs. 1.034 +/- 0.11 g/d). LCT was also observed to induce an elevation of serum bilirubin (1.12 +/- 0.11 mg/dl). These results indicate that MCT-based fat emulsion appears to be a safe energy source.

Hepatitis C virus translation preferentially depends on active RNA replication.

Hepatitis C virus (HCV) RNA initiates its replication on a detergent-resistant membrane structure derived from the endoplasmic reticulum (ER) in the HCV replicon cells. By performing a pulse-chase study of BrU-labeled HCV RNA, we found that the newly-synthesized HCV RNA traveled along the anterograde-membrane traffic and moved away from the ER. Presumably, the RNA moved to the site of translation or virion assembly in the later steps of viral life cycle. In this study, we further addressed how HCV RNA translation was regulated by HCV RNA trafficking. When the movement of HCV RNA from the site of RNA synthesis to the Golgi complex was blocked by nocodazole, an inhibitor of ER-Golgi transport, HCV protein translation was surprisingly enhanced, suggesting that the translation of viral proteins occurred near the site of RNA synthesis. We also found that the translation of HCV proteins was dependent on active RNA synthesis: inhibition of viral RNA synthesis by an NS5B inhibitor resulted in decreased HCV viral protein synthesis even when the total amount of intracellular HCV RNA remained unchanged. Furthermore, the translation activity of the replication-defective HCV replicons or viral RNA with an NS5B mutation was greatly reduced as compared to that of the corresponding wildtype RNA. By performing live cell labeling of newly synthesized HCV RNA and proteins, we further showed that the newly synthesized HCV proteins colocalized with the newly synthesized viral RNA, suggesting that HCV RNA replication and protein translation take place at or near the same site. Our findings together indicate that the translation of HCV RNA is coupled to RNA replication and that the both processes may occur at the same subcellular membrane compartments, which we term the replicasome.

IFN-α/ß and autophagy: tug-of-war between HCV and the host.

Hepatitis C virus (HCV) infects approximately 130 million people worldwide. The clinical sequelae of this chronic disease include cirrhosis, functional failure and carcinoma of the liver. HCV induces autophagy, a fundamental cellular process for maintaining homeostasis and mediating innate immune response, and also inhibits autophagic protein degradation and suppresses antiviral immunity. In addition to this ploy, the HCV serine protease composed of the viral non-structural proteins 3/4A (NS3/4A) can enzymatically digest two cellular proteins, mitochondria-associated anti-viral signaling protein (MAVS) and Toll/interleukin-1 receptor domain containing adaptor inducing IFN-ß (TRIF). Since these two proteins are the adaptor molecules in the retinoic acid-inducible gene I (RIG-I) and TLR3 pathways, respectively, their cleavage has been suggested as a pivotal mechanism by which HCV blunts the IFN-α/ß signaling and antiviral responses. Thus far, how HCV perturbs autophagy and copes with IFN-α/ß in the liver remains unclear.

Transgenic expression of entire hepatitis B virus in mice induces hepatocarcinogenesis independent of chronic liver injury.

Hepatocellular carcinoma (HCC), the third leading cause of cancer deaths worldwide, is most commonly caused by chronic hepatitis B virus (HBV) infection. However, whether HBV plays any direct role in carcinogenesis, other than indirectly causing chronic liver injury by inciting the host immune response, remains unclear. We have established two independent transgenic mouse lines expressing the complete genome of a mutant HBV ("preS2 mutant") that is found at much higher frequencies in people with HCC than those without. The transgenic mice show evidence of stress in the endoplasmic reticulum (ER) and overexpression of cyclin D1 in hepatocytes. These mice do not show any evidence of chronic liver injury, but by 2 years of age a majority of the male mice develop hepatocellular neoplasms, including HCC. Unexpectedly, we also found a significant increase in hepatocarcinogenesis independent of necroinflammation in a transgenic line expressing the entire wildtype HBV. As in the mutant HBV mice, HCC was found only in aged--2-year-old--mice of the wildtype HBV line. The karyotype in all the three transgenic lines appears normal and none of the integration sites of the HBV transgene in the mice is near an oncogene or tumor suppressor gene. The significant increase of HCC incidence in all the three transgenic lines--expressing either mutant or wildtype HBV--therefore argues strongly that in absence of chronic necroinflammation, HBV can contribute directly to the development of HCC.

PKC delta signaling: a dual role in regulating hypoxic stress-induced autophagy and apoptosis.

The protein kinase C (PKC) family of serine/threonine kinases regulates diverse cellular function, including cell death, proliferation and survival. In particular, PKC delta governs the cellular homeostatic response against hypoxic stress. Autophagy, a lysosome-dependent degradative pathway, and apoptosis are two fundamental cellular pathways that respond to stress conditions, such as hypoxia, oxidative stress and nutrient starvation. Recently, we uncovered a novel role for PKC delta in the early stage of hypoxic response where PKC delta activates autophagy by promoting JNK1-mediated Bcl-2 phosphorylation and dissociation of the Bcl-2/Beclin 1 complex. Whereas acute hypoxic stress promotes autophagy, we have previously reported that prolonged hypoxic stress caused the cleavage of PKC delta by caspase-3, resulting in the nuclear translocation of a constitutively active catalytic fragment of PKC delta, PKC delta-CF. Moreover, PKC delta-CF also serves a feed-forward function for the reciprocal PKC delta and caspase-3 proteolytic activation. Here, we discussed the requirement for PKC delta and JNK1 for hypoxia-induced autophagy, and the kinetic relationship among Bcl-2/Beclin 1 interaction, caspase-3 activation and the steady-state level of Beclin 1 during hypoxic exposure. Based on these results, we propose a model for understanding the PKC delta-dependent crosstalk mechanisms between autophagy and apoptosis, both induced by hypoxic stress. These findings collectively support a pivotal role for PKC delta in regulating hypoxic stress with hitherto unappreciated significance.