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A Negative Feedback Loop of the TOR Signaling Moderates Growth And bioRxiv preprint doi: https://doi.org/10.1101/2020.09.06.284745; this version posted September 7, 2020. The copyright holder for this preprint (which was not certified by peer review) is the author/funder. All rights reserved. No reuse allowed without permission. 1 A negative feedback loop of the TOR signaling moderates 2 growth and enables rapid sensing of stress signals in plants 3 Muhammed Jamsheer K1#*<, Sunita Jindal1#>, Mohan Sharma1, Manvi Sharma1, Sreejath Sivaj2, 4 Chanchal Thomas Mannully1^, Ashverya Laxmi1* 5 1National Institute of Plant Genome Research, Aruna Asaf Ali Marg, New Delhi 110067, India 6 2Department of Mechanical Engineering, Indian Institute of Technology Delhi, New Delhi, 110016, 7 India 8 9 <Current affiliation: Amity Food & Agriculture Foundation, Amity University Uttar Pradesh, Sector 10 125, Noida 201313, India 11 ^Current affiliation: Cell Metabolism Laboratory, School of Pharmacy, The Hebrew University of 12 Jerusalem, Jerusalem, 9112102, Israel 13 >Current affiliation: Department of Molecular Biology and Radiology, Mendel University in Brno, 14 Brno, 613 00, Czech Republic 15 16 #Equal first authors 17 18 *Corresponding authors 19 Ashverya Laxmi 20 Muhammed Jamsheer K 21 Email: AL: [email protected] (Lead Contact); MJK: [email protected] 22 ORCID: Ashverya Laxmi (0000-0002-3430-4200); Muhammed Jamsheer K (0000-0002-2135- 23 8760) 24 25 26 27 28 29 30 31 32 33 1 bioRxiv preprint doi: https://doi.org/10.1101/2020.09.06.284745; this version posted September 7, 2020. The copyright holder for this preprint (which was not certified by peer review) is the author/funder. All rights reserved. No reuse allowed without permission. 34 35 ABSTRACT 36 37 TOR kinase is a central coordinator of nutrient-dependent growth in eukaryotes. Maintaining 38 optimal TOR signaling is critical for the normal development of organisms. However, the 39 mechanisms involved in the maintenance of optimal TOR signaling are currently unknown in 40 plants. In this study, we describe a negative feedback loop of TOR signaling helping in the 41 adaptability of plants in changing environmental conditions. Using an interdisciplinary approach, 42 we identified a plant-specific zinc finger protein FLZ8, as a regulator of TOR signaling in 43 Arabidopsis. In sugar sufficiency, FLZ8 is upregulated by TOR-dependent and –independent 44 histone modifications. FLZ8 negatively regulates TOR signaling by promoting antagonistic 45 SnRK1α1 signaling and bridging the interaction of SnRK1α1 with RAPTOR, a crucial accessory 46 protein of TOR. This negative feedback loop moderates the TOR-growth signaling axis in the 47 favorable condition and helps in the rapid activation of stress signaling in unfavorable conditions 48 establishing its importance in the adaptability of plants. 49 50 51 52 53 KEYWORDS 54 Nutrient Signaling, Target Of Rapamycin, SNF1-Related protein Kinase 1, FCS-Like Zinc finger 8, 55 Negative feedback loop, Growth-stress response trade-offs 56 57 58 59 60 61 62 63 64 65 66 67 68 69 2 bioRxiv preprint doi: https://doi.org/10.1101/2020.09.06.284745; this version posted September 7, 2020. The copyright holder for this preprint (which was not certified by peer review) is the author/funder. All rights reserved. No reuse allowed without permission. 70 INTRODUCTION 71 Organisms need to coordinate their growth according to nutrient availability. The Target Of 72 Rapamycin (TOR) kinase works as a central regulator of growth in nutrient sufficiency1,2. Sugar 73 and other nutrients (nitrogen, amino acids, phosphate, etc.) activate TOR complex 1 (TORC1), 74 which is composed of TOR and the accessory proteins, Regulatory-associated protein of TOR 75 (RAPTOR) and Lethal with Sec Thirteen 8 (LST8)1. TORC1 promotes general anabolism and 76 growth2. Nutrient starvation especially the sugar starvation, activates AMP-activated protein 77 kinase (AMPK) which reprograms the growth according to the available nutrients3. The plant 78 homolog of AMPK is known as Snf1-related protein kinase 1 (SnRK1) is found to be a master 79 regulator of growth in sugar starvation indicating the functional conservation of this pathway4. 80 AMPK/SnRK1 phosphorylates RAPTOR leading to the suppression of TOR during starvation5,6. 81 Recently, TORC1 was found to suppress AMPK activity through the direct phosphorylation of its 82 α kinase subunit during starvation7. Thus, the double-negative feedback loop between TOR and 83 AMPK/SnRK1 coordinates growth in eukaryotes according to nutrient availability1. 84 85 TOR is an essential gene and disruption of TOR causes lethal defects in embryo 86 development in plants8,9. Further, TOR is highly expressed in the primary meristems and drives 87 post-embryonic growth in plants8. TOR is also essential for the light and sugar-dependent 88 activation of the meristems through E2F transcription factors10–12. Light perception leads to the 89 activation of TOR and photomorphogenesis11,13. Thus, TOR works as a critical integrator of light 90 and sugar signals to drive post-embryonic growth. TOR is important for the sugar-dependent 91 hypocotyl elongation in dark indicating its role in skotomorphogenesis14. 92 93 Hyperactivation of TOR results in severe developmental abnormalities in plants and 94 animals9,15. Thus, organisms need to maintain optimal TOR activity for normal development. In 95 animals, TORC1 activates the transcription of Sestrins (SESNs) which promotes AMPK leading to 96 the attenuation of TORC1 signaling16,17. The GATOR1 complex prevents the hyperactivation of 97 TORC1 during amino acid sufficiency18. These negative feedback regulators which prevent 98 TORC1 hyperactivity are absent in the plant lineage19,20. Thus, plants possibly have evolved 99 plant-specific mechanisms to moderate TOR signaling. However, such regulators are yet to be 100 discovered in plants. 101 102 The developing seedlings need to maintain a critical level of TOR activity for cell division 103 and organogenesis. At the same time, they are exposed to various stress factors in the 104 environment. Rapid sensing of stress signals and induction of stress response pathways are 105 crucial for the survival of plants on land21. The high TOR activity can attenuate the stress 3 bioRxiv preprint doi: https://doi.org/10.1101/2020.09.06.284745; this version posted September 7, 2020. The copyright holder for this preprint (which was not certified by peer review) is the author/funder. All rights reserved. No reuse allowed without permission. 106 response machinery1,22; therefore, plants need to maintain a homeostasis between the activities 107 of TOR and stress signaling to balance growth and stress responses. 108 109 In this study, we used an interdisciplinary approach to study the importance of 110 mechanisms that regulate TOR signaling to balance growth and stress signaling in plants. 111 Through a data-driven systems biology approach, we identified potential regulatory factors of 112 TOR signaling. We found that one of such factors identified from the screening, FCS-Like Zinc 113 Finger 8 (FLZ8), acts in a negative feedback loop in TOR signaling and maintains basal SnRK1 114 and ABA signaling. This regulation was found to be important in moderating growth and rapid 115 activation of stress signaling in plants. 116 117 RESULTS 118 119 Negative feedback regulation of TOR signaling improves fitness of plants in a fluctuating 120 environment 121 How plants regulate TOR activity to rapidly adjust their growth according to the fluctuations in the 122 environment is not well understood. Negative feedback loops are important in preventing 123 hyperactivation of specific signaling nodes and maintaining homeostasis in cell signaling 124 networks23,24. To understand the significance of negative feedback loops in the TOR signaling in 125 plants, we first employed a mathematical modeling approach as it is a powerful tool to decipher 126 the complex and often counter-intuitive dynamics in the cell signaling networks25. The mutually 127 antagonistic interaction of TOR and ABA signaling is well understood at the molecular level22; 128 therefore, we developed a simple network model for TOR-ABA signaling to understand how 129 plants regulate TOR signaling under different environmental conditions with and without a 130 negative feedback loop denoted as X (Fig. 1A). We used this model to simulate TOR signaling 131 activation and growth progression under energy sufficiency in a system assumed to have 132 baseline TOR and ABA signaling. The negative feedback loop which is activated by TOR under 133 nutrient sufficiency downregulated TOR activity over time leading to the moderation of growth 134 (Fig. 1B, C). We then asked the relevance of such a feedback loop in regulating stress response 135 in changing environmental conditions. In environment, plants that are growing in favorable 136 conditions with high TOR activity can be suddenly exposed to stress conditions. Therefore, we 137 simulated the ABA signaling activation and stress survivability in response to sudden exposure to 138 stress in a system assumed to have high TOR and baseline ABA signaling. The simulation 139 predicted that the presence of X helps in the rapid activation of the stress signaling module which 140 increased the chance of survival (Fig. 1D, E). Taken together, the simulation of the TOR and 141 stress signaling network under different environmental conditions suggest that the negative 4 bioRxiv preprint doi: https://doi.org/10.1101/2020.09.06.284745; this version posted September 7, 2020. The copyright holder for this preprint (which was not certified by peer review) is the author/funder. All rights reserved. No reuse allowed without permission. 142 feedback regulation of TOR signaling would facilitate plants in adjusting their growth in a 143 changing environment. 144 Data-driven screening identifies potential negative feedback regulators of TOR signaling 145 To identify the negative feedback regulators of TOR, we adopted a data-driven screening 146 approach. We constructed an Arabidopsis TOR signaling network by integrating all the interactors 147 and phosho-substrates of TOR complex identified from individual and high-throughput omics 148 studies (Fig.
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