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1. Sestrin2 Phosphorylation by ULK1 Induces Autophagic Degradation of Mitochondria Damaged by Copper-Induced Oxidative Stress

   https://doi.org/10.3390/ijms21176130  

   Kim, Heejeong ; Jeon, Byeong Tak ; Kim, Isaac M. ; Bennett, Sydney J. ; Lorch, Carolyn M. ; Viana, Martonio Ponte ; Myers, Jacob F. ; Trupp, Caroline J. ; Whipps, Zachary T. ; Kundu, Mondira ; et al ( September 2020 , International Journal of Molecular Sciences)

   null (Ed.)

   Selective autolysosomal degradation of damaged mitochondria, also called mitophagy, is an indispensable process for maintaining integrity and homeostasis of mitochondria. One well-established mechanism mediating selective removal of mitochondria under relatively mild mitochondria-depolarizing stress is PINK1-Parkin-mediated or ubiquitin-dependent mitophagy. However, additional mechanisms such as LC3-mediated or ubiquitin-independent mitophagy induction by heavy environmental stress exist and remain poorly understood. The present study unravels a novel role of stress-inducible protein Sestrin2 in degradation of mitochondria damaged by transition metal stress. By utilizing proteomic methods and studies in cell culture and rodent models, we identify autophagy kinase ULK1-mediated phosphorylation sites of Sestrin2 and demonstrate Sestrin2 association with mitochondria adaptor proteins in HEK293 cells. We show that Ser-73 and Ser-254 residues of Sestrin2 are phosphorylated by ULK1, and a pool of Sestrin2 is strongly associated with mitochondrial ATP5A in response to Cu-induced oxidative stress. Subsequently, this interaction promotes association with LC3-coated autolysosomes to induce degradation of mitochondria damaged by Cu-induced ROS. Treatment of cells with antioxidants or a Cu chelator significantly reduces Sestrin2 association with mitochondria. These results highlight the ULK1-Sestrin2 pathway as a novel stress-sensing mechanism that can rapidly induce autophagic degradation of mitochondria under severe heavy metal stress. 

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2. Function of the pseudo phosphotransfer proteins has diverged between rice and Arabidopsis

   https://doi.org/10.1111/tpj.15156  

   Vaughan‐Hirsch, John ; Tallerday, Emily J. ; Burr, Christian A. ; Hodgens, Charlie ; Boeshore, Samantha L. ; Beaver, Kevin ; Melling, Allison ; Sari, Kartika ; Kerr, Ian D. ; Šimura, Jan ; et al ( February 2021 , The Plant Journal)

   The phytohormone cytokinin plays a significant role in nearly all aspects of plant growth and development. Cytokinin signaling has primarily been studied in the dicot model Arabidopsis, with relatively little work done in monocots, which include rice (Oryza sativa) and other cereals of agronomic importance. The cytokinin signaling pathway is a phosphorelay comprised of the histidine kinase receptors, the authentic histidine phosphotransfer proteins (AHPs) and type‐B response regulators (RRs). Two negative regulators of cytokinin signaling have been identified: the type‐A RRs, which are cytokinin primary response genes, and the pseudo histidine phosphotransfer proteins (PHPs), which lack the His residue required for phosphorelay. Here, we describe the role of the ricePHPgenes. Phylogenic analysis indicates that the PHPs are generally first found in the genomes of gymnosperms and that they arose independently in monocots and dicots. Consistent with this, the three ricePHPsfail to complement an Arabidopsisphpmutant (aphp1/ahp6). Disruption of the three ricePHPsresults in a molecular phenotype consistent with these elements acting as negative regulators of cytokinin signaling, including the induction of a number of type‐A RR and cytokinin oxidase genes. The triplephpmutant affects multiple aspects of rice growth and development, including shoot morphology, panicle architecture, and seed fill. In contrast to Arabidopsis, disruption of the ricePHPsdoes not affect root vascular patterning, suggesting that while many aspects of key signaling networks are conserved between monocots and dicots, the roles of at least some cytokinin signaling elements are distinct.

    

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3. Cytokinin‐induced protein synthesis suppresses growth and osmotic stress tolerance

   https://doi.org/10.1111/nph.16519  

   Karunadasa, Sumudu S. ; Kurepa, Jasmina ; Shull, Timothy E. ; Smalle, Jan A. ( April 2020 , New Phytologist)

   Cytokinins control critical aspects of plant development and environmental responses. Perception of cytokinin ultimately leads to the activation of proteins belonging to the type‐B Response Regulator family of cytokinin response activators. InArabidopsis thaliana, ARR1 is one of the most abundantly expressed type‐B Response Regulators.

   We investigated the link between cytokinin signaling, protein synthesis, plant growth and osmotic stress tolerance.

   We show that the increased cytokinin signaling in ARR1 gain‐of‐function transgenic lines is associated with increased rates of protein synthesis, which lead to growth inhibition and hypersensitivity to osmotic stress. Cytokinin‐induced growth inhibition and osmotic stress hypersensitivity were rescued by treatments with ABA, a hormone known to inhibit protein synthesis. We also demonstrate that cytokinin‐induced protein synthesis requires isoforms of the ribosomal protein L4 encoded by the cytokinin‐inducible genesRPL4AandRPL4D, and thatRPL4loss‐of‐function increases osmotic stress tolerance and decreases sensitivity to cytokinin‐induced growth inhibition.

   These findings reveal that an increase in protein synthesis negatively impacts growth and osmotic stress tolerance and explain some of the adverse effects of elevated cytokinin action on plant development and stress physiology.

    

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4. Downregulation of PHLPP induced by endoplasmic reticulum stress promotes eIF2α phosphorylation and chemoresistance in colon cancer

   https://doi.org/10.1038/s41419-021-04251-0  

   Guo, Bianqin ; Xiong, Xiaopeng ; Hasani, Sumati ; Wen, Yang-An ; Li, Austin T. ; Martinez, Rebecca ; Skaggs, Ashley T. ; Gao, Tianyan ( October 2021 , Cell Death & Disease)

   Aberrant activation of endoplasmic reticulum (ER) stress by extrinsic and intrinsic factors contributes to tumorigenesis and resistance to chemotherapies in various cancer types. Our previous studies have shown that the downregulation of PHLPP, a novel family of Ser/Thr protein phosphatases, promotes tumor initiation, and progression. Here we investigated the functional interaction between the ER stress and PHLPP expression in colon cancer. We found that induction of ER stress significantly decreased the expression of PHLPP proteins through a proteasome-dependent mechanism. Knockdown of PHLPP increased the phosphorylation of eIF2α as well as the expression of autophagy-associated genes downstream of the eIF2α/ATF4 signaling pathway. In addition, results from immunoprecipitation experiments showed that PHLPP interacted with eIF2α and this interaction was enhanced by ER stress. Functionally, knockdown of PHLPP improved cell survival under ER stress conditions, whereas overexpression of a degradation-resistant mutant PHLPP1 had the opposite effect. Taken together, our studies identified ER stress as a novel mechanism that triggers PHLPP downregulation; and PHLPP-loss promotes chemoresistance by upregulating the eIF2α/ATF4 signaling axis in colon cancer cells.

    

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5. SMOC-1 interacts with both BMP and glypican to regulate BMP signaling in C. elegans

   https://doi.org/10.1371/journal.pbio.3002272  

   DeGroot, Melisa S. ; Williams, Byron ; Chang, Timothy Y. ; Maas Gamboa, Maria L. ; Larus, Isabel M. ; Hong, Garam ; Fromme, J. Christopher ; Liu, Jun ( August 2023 , PLOS Biology)

   Mullins, Mary C. (Ed.)

   Secreted modular calcium-binding proteins (SMOCs) are conserved matricellular proteins found in organisms fromCaenorhabditis elegansto humans. SMOC homologs characteristically contain 1 or 2 extracellular calcium-binding (EC) domain(s) and 1 or 2 thyroglobulin type-1 (TY) domain(s). SMOC proteins inDrosophilaandXenopushave been found to interact with cell surface heparan sulfate proteoglycans (HSPGs) to exert both positive and negative influences on the conserved bone morphogenetic protein (BMP) signaling pathway. In this study, we used a combination of biochemical, structural modeling, and molecular genetic approaches to dissect the functions of the sole SMOC protein inC.elegans. We showed that CeSMOC-1 binds to the heparin sulfate proteoglycan GPC3 homolog LON-2/glypican, as well as the mature domain of the BMP2/4 homolog DBL-1. Moreover, CeSMOC-1 can simultaneously bind LON-2/glypican and DBL-1/BMP. The interaction between CeSMOC-1 and LON-2/glypican is mediated specifically by the EC domain of CeSMOC-1, while the full interaction between CeSMOC-1 and DBL-1/BMP requires full-length CeSMOC-1. We provide both in vitro biochemical and in vivo functional evidence demonstrating that CeSMOC-1 functions both negatively in a LON-2/glypican-dependent manner and positively in a DBL-1/BMP-dependent manner to regulate BMP signaling. We further showed that in silico,Drosophilaand vertebrate SMOC proteins can also bind to mature BMP dimers. Our work provides a mechanistic basis for how the evolutionarily conserved SMOC proteins regulate BMP signaling.

    

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