Endoplasmic reticulum (ER) stress is involved in many cellular processes. Emerging evidence suggests that ER stress can trigger autophagy; however, the mechanisms by which ER stress regulates autophagy and its role in this condition are not fully understood. HIV Tat-interactive protein, 60 kDa (TIP60) is a newly discovered acetyltransferase that can modulate autophagy flux by activating ULK1 upon growth factor deprivation. In this study, we investigated the mechanisms by which ER stress induces autophagy. We showed that ER stress activates glycogen synthase kinase-3β (GSK3β). This led to a GSK3β-dependent phosphorylation of TIP60, triggering a TIP60-mediated acetylation of ULK1 and activation of autophagy. Inhibition of either GSK3β or TIP60 acetylation activities significantly attenuated ER stress-induced autophagy. Moreover, enhancing the level of TIP60 attenuated the level of CHOP after ER stress, and reduced the ER stress-induced cell death. In contrast, expression of TIP60 mutant that could not be phosphorylated by GSK3β exacerbated the generation of CHOP and increased the ER stress-induced cell death. These findings reveal that ER stress engages the GSK3β-TIP60-ULK1 pathway to increase autophagy. Attenuation of this pathway renders cells more sensitive to and increases the toxicity of ER stress.
State Key Laboratory of Bioactive Molecules and Druggability Assessment, International Cooperative Laboratory of Traditional Chinese Medicine Modernization and Innovative Drug Development of Chinese Ministry of Education (MOE) of China, School of Pharmacy, Jinan University, Guangzhou, China.
Background: Stomach adenocarcinoma (STAD) is an aggressive malignancy characterized by high tumor plasticity and heterogeneity. This study investigates the role of Autophagy and Beclin 1 Regulator 1 (AMBRA1) in regulating tumor plasticity in STAD progression.
Methods: Combined with clinical data, the pan-cancer analysis of AMBRA1 was performed to analyze the role of AMBRA1 in STAD.
Sepsis is characterized by a concomitant early pro-inflammatory response by immune cells to an infection, and an opposing anti-inflammatory response that results in protracted immunosuppression. The primary pathological event in sepsis is widespread programmed cell death, or cellular self-sacrifice, of innate and adaptive immune cells, leading to profound immunological suppression. This severe immune dysfunction hampers effective primary pathogen clearance, thereby increasing the risk of secondary opportunistic infections, latent viral reactivation, multiple organ dysfunction, and elevated mortality.
Accumulating evidence demonstrates that alpha-synuclein (α-syn) pathology associated with Parkinson's disease (PD) is not limited to the brain, as it also appears in a select number of peripheral tissues including the liver. In this study, we identified a number of PD-associated α-syn post-translational modifications in the livers of (Thy-1)-h[A30P] mice, a mouse model of familial PD expressing human α-syn harboring the A30P mutation driven by a neuron-specific promoter. , we also demonstrate that human hepatocytes induce post-translational modifications following α-syn fibrillar (PFF) treatment.
Autophagy-lysosomal degradation is a conserved homeostatic process considered to be crucial for cardiac morphogenesis. However, both its cell specificity and functional role during heart development remain unclear. Here, we introduced zebrafish models to visualize autophagic vesicles and track their temporal and cellular localization in the larval heart.
Introduction: Neutrophil autophagy and neutrophil extracellular trap (NET) formation are closely related to asthma pathogenesis. Src homology domain 2-containing protein tyrosine phosphatase 2 (SHP2) is an important regulatory factor in airway remodeling in asthma. This study aimed to explore the molecular mechanisms of SHP2 in neutrophils.
