A multicomponent macrocyclization strategy towards cyclic lipopeptides is described. The approach relies on the utilization of the Ugi and Passerini multicomponent reactions for the cyclization of peptides and oxo-peptides, and here it is employed for the construction of a small library of analogues of the natural products mycosubtilin and surfactin A. A key feature of this method is the simultaneous incorporation of either one or two exocyclic lipid tails along with the macrocyclic ring closure, which is only possible due to the multicomponent nature of the macrocyclization step. The evaluation of the anticancer activity of the lipopeptide library showed that the installation of a second lipid moiety in the surfactin scaffold leads to a more potent cytotoxicity in cancer cells. This is a new example of the multicomponent reaction potential in rapidly producing natural product analogues for biological screening.

Proteome remodeling is a fundamental adaptive response, and proteins in complexes and functionally related proteins are often co-expressed. Using a deep sampling strategy we define core proteomes of Arabidopsis thaliana tissues with around 10 000 proteins per tissue, and absolutely quantify (copy numbers per cell) nearly 16 000 proteins throughout the plant lifecycle. A proteome-wide survey of global post-translational modification revealed amino acid exchanges pointing to potential conservation of translational infidelity in eukaryotes. Correlation analysis of protein abundance uncovered potentially new tissue-and agespecific roles of entire signaling modules regulating transcription in photosynthesis, seed development, and senescence and abscission. Among others, the data suggest a potential function of RD26 and other NAC transcription factors in seed development related to desiccation tolerance as well as a possible function of cysteine-rich receptor-like kinases (CRKs) as ROS sensors in senescence. All of the components of ribosome biogenesis factor (RBF) complexes were found to be co-expressed in a tissue-and age-specific manner, indicating functional promiscuity in the assembly of these less-studied protein complexes in Arabidopsis.Furthermore, we characterized detailed proteome remodeling in basal immunity by treating Arabidopsis seeldings with flg22. Through simultaneously monitoring phytohormone and transcript changes upon flg22 treatment, we obtained strong evidence of suppression of jasmonate (JA) and JA-isoleucine (JA-Ile) levels by deconjugation and hydroxylation by IAA-ALA RESISTANT3 (IAR3) and JASMONATE-INDUCED OXYGENASE 2 (JOX2), respectively, under the control of JASMONATE INSENSITIVE 1 (MYC2), suggesting an unrecognized role of a new JA regulatory switch in pattern-triggered immunity. Taken together, the datasets generated in this study present extensive coverage of the Arabidopsis proteome in various biological scenarios, providing a rich resource available to the whole plant science community.

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The RNA–binding protein Musashi–1 (MSI1) promotes stemness during development and cancer. By controlling target mRNA turnover and translation, MSI1 is implicated in the regulation of cancer hallmarks such as cell cycle or Notch signaling. Thereby, the protein enhanced cancer growth and therapy resistance to standard regimes. Due to its specific expression pattern and diverse functions, MSI1 represents an interesting target for cancer therapy in the future. In this review we summarize previous findings on MSI1′s implications in developmental processes of other organisms. We revisit MSI1′s expression in a set of solid cancers, describe mechanistic details and implications in MSI1 associated cancer hallmark pathways and highlight current research in drug development identifying the first MSI1–directed inhibitors with anti–tumor activity.

24Proteome remodeling is a fundamental adaptive response and proteins in complex and 25 functionally related proteins are often co-expressed. Using a deep sampling strategy we 26 define Arabidopsis thaliana tissue core proteomes at around 10,000 proteins per tissue 27 and absolutely quantify (copy numbers per cell) nearly 16,000 proteins throughout the 28 plant lifecycle. A proteome wide survey of global post translational modification revealed 29 amino acid exchanges pointing to potential conservation of translational infidelity in 30 eukaryotes. Correlation analysis of protein abundance uncovered potentially new tissue 31 and age specific roles of entire signaling modules regulating transcription in 32 photosynthesis, seed development and senescence and abscission. Among others, the 33 data suggest a potential function of RD26 and other NAC transcription factors in seed 34 development related to desiccation tolerance as well as a possible function of Cysteine-35 rich Receptor-like Kinases (CRKs) as ROS sensors in senescence. All of the 36 components of ribosome biogenesis factor (RBF) complexes were co-expressed tissue 37 and age specifically indicating functional promiscuity in the assembly of these little 38 described protein complexes in Arabidopsis. Treatment of seedlings with flg22 for 16 39 hours allowed us to characterize proteome architecture in basal immunity in detail. The 40 results were complemented with parallel reaction monitoring (PRM) targeted 41 proteomics, phytohormone, amino acid and transcript measurements. We obtained 42 strong evidence of suppression of jasmonate (JA) and JA-Ile levels by deconjugation 43 and hydroxylation via IAA-ALA RESISTANT3 (IAR3) and JASMONATE-INDUCED 44 OXYGENASE 2 (JOX2) under the control of JASMONATE INSENSITIVE 1 (MYC2). 45 This previously unknown regulatory switch is another part of the puzzle of the as yet 46 understudied role of JA in pattern triggered immunity. The extensive coverage of the 47 Arabidopsis proteome in various biological scenarios presents a rich resource to plant 48 biologists that we make available to the community.49 50 51 52 53 Proteome biology is receiving increasing interest in the last years but still proves difficult 54 on a genome wide scale in plants. The proteome is the most fundamental active 55 determinant of an organism's phenotype and its landscape is large, complex and 56 dynamic, entailing changes in protein abundance, interaction, post translational 57 modification (PTM) and sub-cellular localization. 58 Steady state protein abundance at a certain time point is to a considerable part 59 determined by the abundance of its transcript and the latter's translation rate. Synthesis 60 is however only half of the equation governing protein abundance, indeed Arabidopsis 61 has more than 600 F-box proteins as components of diverse E3 ubiquitin ligase 62 complexes that direct protein degradation. Newer evidence has shown that post 63 transcriptional and translational mechanisms (Ponnala et al., 2014; Merchante et al., 64 2017) and...