bims-ershed 2022-06-12 papers

ACS Chem Biol. 2022 Jun 08.

Monitoring Protein Import into the Endoplasmic Reticulum in Living Cells with Proximity Labeling.

Ziqi Lyu, Melody M Sycks, Mateo F Espinoza, Khanh K Nguyen, Maureen R Montoya, Cheska M Galapate, Liangyong Mei, Joseph C Genereux.

The proper trafficking of eukaryotic proteins is essential to cellular function. Genetic, environmental, and other stresses can induce protein mistargeting and, in turn, threaten cellular protein homeostasis. Current methods for measuring protein mistargeting are difficult to translate to living cells, and thus the role of cellular signaling networks in stress-dependent protein mistargeting processes, such as ER pre-emptive quality control (ER pQC), is difficult to parse. Herein, we use genetically encoded peroxidases to characterize protein import into the endoplasmic reticulum (ER). We show that the ERHRP/cytAPEX pair provides good selectivity and sensitivity for both multiplexed protein labeling and for identifying protein mistargeting, using the known ER pQC substrate transthyretin (TTR). Although ERHRP labeling induces formation of detergent-resistant TTR aggregates, this is minimized by using low ERHRP expression, without loss of labeling efficiency. cytAPEX labeling recovers TTR that is mistargeted as a consequence of Sec61 inhibition or ER stress-induced ER pQC. Furthermore, we discover that stress-free activation of the ER stress-associated transcription factor ATF6 recapitulates the TTR import deficiency of ER pQC. Hence, proximity labeling is an effective strategy for characterizing factors that influence ER protein import in living cells.

DOI: https://doi.org/10.1021/acschembio.2c00405

Int J Mol Sci. 2022 May 24. pii: 5894. [Epub ahead of print]23(11):

The Common Cellular Events in the Neurodegenerative Diseases and the Associated Role of Endoplasmic Reticulum Stress.

Soojeong Kim, Doo Kyung Kim, Seho Jeong, Jaemin Lee.

Neurodegenerative diseases are inseparably linked with aging and increase as life expectancy extends. There are common dysfunctions in various cellular events shared among neurogenerative diseases, such as calcium dyshomeostasis, neuroinflammation, and age-associated decline in the autophagy-lysosome system. However, most of all, the prominent pathological feature of neurodegenerative diseases is the toxic buildup of misfolded protein aggregates and inclusion bodies accompanied by an impairment in proteostasis. Recent studies have suggested a close association between endoplasmic reticulum (ER) stress and neurodegenerative pathology in cellular and animal models as well as in human patients. The contribution of mutant or misfolded protein-triggered ER stress and its associated signaling events, such as unfolded protein response (UPR), to the pathophysiology of various neurodegenerative disorders, including Alzheimer's, Parkinson's, and Huntington's disease, amyotrophic lateral sclerosis, and prion disease, is described here. Impaired UPR action is commonly attributed to exacerbated ER stress, pathogenic protein aggregate accumulation, and deteriorating neurodegenerative pathologies. Thus, activating certain UPR components has been shown to alleviate ER stress and its associated neurodegeneration. However, uncontrolled activation of some UPR factors has also been demonstrated to worsen neurodegenerative phenotypes, suggesting that detailed molecular mechanisms around ER stress and its related neurodegenerations should be understood to develop effective therapeutics against aging-associated neurological syndromes. We also discuss current therapeutic endeavors, such as the development of small molecules that selectively target individual UPR components and address ER stress in general.

Keywords: Alzheimer’s disease; ER stress; Huntington’s disease; Parkinson’s disease; amyotrophic lateral sclerosis; endoplasmic reticulum; misfolded protein; neurodegenerative disease; prion disease; unfolded protein response

DOI: https://doi.org/10.3390/ijms23115894

Expert Opin Drug Discov. 2022 Jun 05. 1-3

A meditation on accelerating the development of small molecule medicines targeting RNA.

Xueyi Yang, Jessica L Childs-Disney, Matthew D Disney.

Keywords: Drug design; RNA; genetically defined disease; precision medicine; small molecules

DOI: https://doi.org/10.1080/17460441.2022.2084528

Genes Dis. 2022 Jul;9(4): 981-999

Emerging roles of activating transcription factor (ATF) family members in tumourigenesis and immunity: Implications in cancer immunotherapy.

Meilin Chen, Yijun Liu, Yuqin Yang, Yanbing Qiu, Zhicheng Wang, Xiaoxu Li, Wenling Zhang.

Activating transcription factors, ATFs, are a group of bZIP transcription factors that act as homodimers or heterodimers with a range of other bZIP factors. In general, ATFs respond to extracellular signals, indicating their important roles in maintaining homeostasis. The ATF family includes ATF1, ATF2, ATF3, ATF4, ATF5, ATF6, and ATF7. Consistent with the diversity of cellular processes reported to be regulated by ATFs, the functions of ATFs are also diverse. ATFs play an important role in cell proliferation, apoptosis, differentiation and inflammation-related pathological processes. The expression and phosphorylation status of ATFs are also related to neurodegenerative diseases and polycystic kidney disease. Various miRNAs target ATFs to regulate cancer proliferation, apoptosis, autophagy, sensitivity and resistance to radiotherapy and chemotherapy. Moreover, ATFs are necessary to maintain cell redox homeostasis. Therefore, deepening our understanding of the regulation and function of ATFs will provide insights into the basic regulatory mechanisms that influence how cells integrate extracellular and intracellular signals into genomic responses through transcription factors. Under pathological conditions, especially in cancer biology and response to treatment, the characterization of ATF dysfunction is important for understanding how to therapeutically utilize ATF2 or other pathways controlled by transcription factors. In this review, we will demonstrate how ATF1, ATF2, ATF3, ATF4, ATF5, ATF6, and ATF7 function in promoting or suppressing cancer development and identify their roles in tumour immunotherapy.

Keywords: ATF; Anti-tumor effect; Cancer; Immunity; Tumorigenesis; bZIP

DOI: https://doi.org/10.1016/j.gendis.2021.04.008