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Parkin is an E3 ubiquitin ligase that mediates the ubiquitination of protein substrates. The mutations in the parkin gene can lead to a loss of function of parkin and cause autosomal recessive juvenile onset parkinsonism. Recently, parkin was reported to be involved in the regulation of mitophagy. Here, we identify the Bcl-2, an anti-apoptotic and autophagy inhibitory protein, as a substrate for parkin. Parkin directly binds to Bcl-2 via its C terminus and mediates the mono-ubiquitination of Bcl-2, which increases the steady-state levels of Bcl-2. Overexpression of parkin, but not its ligase-deficient forms, decreases autophagy marker LC3 conversion, whereas knockdown of parkin increases LC3 II levels. In HeLa cells, a parkin-deficient cell line, knockdown of parkin does not change LC3 conversion. Moreover, overexpression of parkin enhances the interactions between Bcl-2 and Beclin 1. Our results provide evidence that parkin mono-ubiquitinates Bcl-2 and regulates autophagy via Bcl-2. Parkinson disease (PD)2 is the second most common neurodegenerative disorder after Alzheimer disease (1) and is characterized by a distinct set of motor symptoms including tremor, muscle rigidity, postural instability, and bradykinesia (2). Although the cause of PD is poorly understood, there is evidence that both environmental factors and genetic factors contribute to its development. Recently, several genes have been reported to be associated with the pathogenesis of familial forms of PD. Mutations in the parkin gene (PARK2; OMIM600116) cause autosomal recessive juvenile onset parkinsonism (3). It has been shown that mutations in parkin account for nearly 50% of patients with the early onset familial PD cases (3-6) and more than 15% of sporadic PD cases with early onset (7).Parkin is a 465-amino acid protein that contains an ubiquitin-like domain at its N terminus and two RING finger domains separated by an in-between-ring domain at its C terminus. Similar to other RING finger-containing proteins, parkin is an E3 ubiquitin ligase. Parkin ubiquitinates several target proteins and enhances their degradation via the ubiquitin-proteasome system (8, 9). Ubiquitination of a substrate is usually processed by a multi-step involving the sequential activity of an E1 ubiquitin-activating enzyme, an E2 ubiquitin-conjugating enzyme, and an E3 ubiquitin-protein ligase (10). It was reported that parkin can selectively interact with the E2 enzymes, UbcH7 and UbcH8 (9,11,12). A number of protein substrates for parkin have been identified, including synphilin-1 (13, 14), CDCrel-1 and 2a (12, 15), Pael-R (16), synaptotagmin XI (17), ␣-and ␤-tubulin (18), RanBP2 (19), cyclin E (20), the aminoacyl-tRNA synthetase cofactor p38/AIMP2 (21, 22), Eps15 (23), and far upstream sequence element-binding protein 1 (24). Within these substrates, p38/AIMP2 and far upstream sequence element-binding protein 1 were reported to be accumulated in brains of parkin null mice, MPTP (1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine) treated mice, and sporadic PD cases (22,24)...

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The goal of our study is to evaluate the effect of Scutellarin on type II diabetes-induced testicular disorder and show the mechanism of Scutellarin's action. We used streptozotocin and high-fat diet to establish type II diabetic rat model. TUNEL and haematoxylin and eosin staining were used to evaluate the testicular apoptotic cells and morphologic changes. Immunohistochemical staining was used to measure the expression level of vascular endothelial growth factor and blood vessel density in testes. Oxidative stress in testes and epididymis was tested by fluorescence spectrophotometer and ELISA. The expression of Bcl-2/Bax and blood flow rate in testicular vessels were measured by western blot and Doppler. Our results for the first time showed that hyperglycemia induced apoptotic cells and morphologic impairments in testes of rats, while administration of Scutellarin can significantly inhibit these damages. This effect of Scutellarin is controlled by two apoptotic triggers: ROS/Bcl-2/Bax and ROS/microcirculation/starving pathway.

Global warming increases sea temperature and leads to high temperature stress, which affects the yield and quality of Pyropia haitanensis. To understand the molecular mechanisms underlying high temperature stress in a high temperature tolerance strain Z-61, the iTRAQ technique was employed to reveal the global proteomic response of Z-61 under different durations of high temperature stress. We identified 151 differentially expressed proteins and classified them into 11 functional categories. The 4 major categories of these are protein synthesis and degradation, photosynthesis, defense response, and energy and carbohydrate metabolism. These findings indicated that photosynthesis, protein synthesis, and secondary metabolism are inhibited by heat to limit damage to a repairable level. As time progresses, misfolded proteins and ROS accumulate and lead to the up-regulation of molecular chaperones, proteases, and antioxidant systems. Furthermore, to cope with cells injured by heat, PCD works to remove them. Additionally, sulfur assimilation and cytoskeletons play essential roles in maintaining cellular and redox homeostasis. These processes are based on signal transduction in the phosphoinositide pathway and multiple ways to supply energy. Conclusively, Z-61 establishes a new steady-state balance of metabolic processes and survives under higher temperature stress.

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