bims-nucpor 2021-05-09 papers

Issue of 2021–05–09
five papers selected by
Sara Mingu, Johannes Gutenberg University

Plant Cell. 2021 May 05. 33(3): 697-713

Exportin-4 coordinates nuclear shuttling of TOPLESS family transcription corepressors to regulate plant immunity.

Feifei Xu, Min Jia, Xin Li, Yu Tang, Keni Jiang, Jinsong Bao, Yangnan Gu.

The regulated nucleocytoplasmic exchange of macromolecules is essential for the eukaryotic cell. However, nuclear transport pathways defined by different nuclear transport receptors (NTRs), including importins and exportins, and their significance in activating distinct stress responses are poorly understood in plants. Here, we exploited a CRISPR/Cas9-based genetic screen to search for modifiers of CONSTITUTIVE EXPRESSION OF PATHOGENESIS-RELATED GENE 5 (cpr5), an Arabidopsis thaliana nucleoporin mutant that activates autoimmune responses that partially mimic effector-triggered immunity (ETI). We identified an NTR gene, Exportin-4 (XPO4), as a genetic interactor of CPR5. The xpo4 cpr5 double mutant activates catastrophic immune responses, which leads to seedling lethality. By leveraging the newly developed proximity-labeling proteomics, we profiled XPO4 substrates and identified TOPLESS (TPL) and TPL-related (TPR) transcription corepressors as XPO4-specific cargo. TPL/TPRs target negative regulators of immunity and are redundantly required for ETI induction. We found that loss-of-XPO4 promotes the nuclear accumulation of TPL/TPRs in the presence of elevated salicylic acid (SA), which contributes to the SA-mediated defense amplification and potentiates immune induction in the cpr5 mutant. We showed that TPL and TPRs are required for the enhanced immune activation observed in xpo4 cpr5 but not for the cpr5 single-mutant phenotype, underscoring the functional interplay between XPO4 and TPL/TPRs and its importance in cpr5-dependent immune induction. We propose that XPO4 coordinates the nuclear accumulation of TPL/TPRs, which plays a role in regulating SA-mediated defense feedback to modulate immune strength downstream of CPR5 during ETI induction.

DOI: https://doi.org/10.1093/plcell/koaa047

Cells. 2021 Apr 29. pii: 1054. [Epub ahead of print]10(5):

Manifestations of Age on Autophagy, Mitophagy and Lysosomes in Skeletal Muscle.

Matthew Triolo, David A Hood.

Sarcopenia is the loss of both muscle mass and function with age. Although the molecular underpinnings of sarcopenia are not fully understood, numerous pathways are implicated, including autophagy, in which defective cargo is selectively identified and degraded at the lysosome. The specific tagging and degradation of mitochondria is termed mitophagy, a process important for the maintenance of an organelle pool that functions efficiently in energy production and with relatively low reactive oxygen species production. Emerging data, yet insufficient, have implicated various steps in this pathway as potential contributors to the aging muscle atrophy phenotype. Included in this is the lysosome, the end-stage organelle possessing a host of proteolytic and degradative enzymes, and a function devoted to the hydrolysis and breakdown of defective molecular complexes and organelles. This review provides a summary of our current understanding of how the autophagy-lysosome system is regulated in aging muscle, highlighting specific areas where knowledge gaps exist. Characterization of the autophagy pathway with a particular focus on the lysosome will undoubtedly pave the way for the development of novel therapeutic strategies to combat age-related muscle loss.

Keywords: aging; autophagy; lysosomes; mitophagy; sarcopenia; skeletal muscle

DOI: https://doi.org/10.3390/cells10051054

Free Radic Biol Med. 2021 Apr 30. pii: S0891-5849(21)00260-4. [Epub ahead of print]169 382-396

mTOR in Alzheimer disease and its earlier stages: Links to oxidative damage in the progression of this dementing disorder.

M Perluigi, F Di Domenico, E Barone, D A Butterfield.

Alzheimer's disease (AD) is the most prevalent form of dementia in the elderly population and has worldwide impact. The etiology of the disease is complex and results from the confluence of multiple mechanisms ultimately leading to neuronal loss and cognitive decline. Among risk factors, aging is the most relevant and accounts for several pathogenic events that contribute to disease-specific toxic mechanisms. Accumulating evidence linked the alterations of the mammalian target of rapamycin (mTOR), a serine/threonine protein kinase playing a key role in the regulation of protein synthesis and degradation, to age-dependent cognitive decline and pathogenesis of AD. To date, growing studies demonstrated that aberrant mTOR signaling in the brain affects several pathways involved in energy metabolism, cell growth, mitochondrial function and proteostasis. Recent advances associated alterations of the mTOR pathway with the increased oxidative stress. Disruption of all these events strongly contribute to age-related cognitive decline including AD. The current review discusses the main regulatory roles of mTOR signaling network in the brain, focusing on its role in autophagy, oxidative stress and energy metabolism. Collectively, experimental data suggest that targeting mTOR in the CNS can be a valuable strategy to prevent/slow the progression of AD.

Keywords: Alzheimer's disease; Oxidative stress; Protein aggregation; Proteostasis; mTOR

DOI: https://doi.org/10.1016/j.freeradbiomed.2021.04.025

Adv Geriatr Med Res. 2021 ;pii: e210010. [Epub ahead of print]3(2):

Organelle-Specific Autophagy in Cellular Aging and Rejuvenation.

Tyler J Butsch, Bhaswati Ghosh, K Adam Bohnert.

The health of a cell requires proper functioning, regulation, and quality control of its organelles, the membrane-enclosed compartments inside the cell that carry out its essential biochemical tasks. Aging commonly perturbs organelle homeostasis, causing problems to cellular health that can spur the initiation and progression of degenerative diseases and related pathologies. Here, we discuss emerging evidence indicating that age-related defects in organelle homeostasis stem in part from dysfunction of the autophagy-lysosome system, a pivotal player in cellular quality control and damage clearance. We also highlight natural examples from biology where enhanced activity of the autophagy-lysosome system might be harnessed to erase age-related organelle damage, raising potential implications for cellular rejuvenation.

Keywords: aging; autophagy; cell biology; organelles; rejuvenation

DOI: https://doi.org/10.20900/agmr20210010

Genetics. 2019 Oct 01. 213(2): 329-360

TOR Signaling in Caenorhabditis elegans Development, Metabolism, and Aging.

T Keith Blackwell, Aileen K Sewell, Ziyun Wu, Min Han.

The Target of Rapamycin (TOR or mTOR) is a serine/threonine kinase that regulates growth, development, and behaviors by modulating protein synthesis, autophagy, and multiple other cellular processes in response to changes in nutrients and other cues. Over recent years, TOR has been studied intensively in mammalian cell culture and genetic systems because of its importance in growth, metabolism, cancer, and aging. Through its advantages for unbiased, and high-throughput, genetic and in vivo studies, Caenorhabditis elegans has made major contributions to our understanding of TOR biology. Genetic analyses in the worm have revealed unexpected aspects of TOR functions and regulation, and have the potential to further expand our understanding of how growth and metabolic regulation influence development. In the aging field, C. elegans has played a leading role in revealing the promise of TOR inhibition as a strategy for extending life span, and identifying mechanisms that function upstream and downstream of TOR to influence aging. Here, we review the state of the TOR field in C. elegans, and focus on what we have learned about its functions in development, metabolism, and aging. We discuss knowledge gaps, including the potential pitfalls in translating findings back and forth across organisms, but also describe how TOR is important for C. elegans biology, and how C. elegans work has developed paradigms of great importance for the broader TOR field.

Keywords: Caenorhabditis elegans development; DAF-15; NPRL-2; NPRL-3; Nprl2; Nprl3; RAGA-1; RSKS-1; RagA; RagC; Raptor; Rheb; Rheb-1; Rictor; S6 kinase; TOR; TORC1; TORC2; WormBook; aging; growth regulation; metabolism; nutrient signaling; sphingolipid

DOI: https://doi.org/10.1534/genetics.119.302504