Global Analysis of Intercellular Homeodomain Protein Transfer

Lee, Eun Jung; Kim, Namsuk; Park, Jun Woo; Kang, Kyung‐Hwa; Kim, Woo Il; Sim, Nam Suk; Jeong, Chan Seok; Blackshaw, Seth; Vidal, Marc; Huh, Sung‐Oh; Kim, Dongsup; Lee, Jehee; Kim, Jin Woo

doi:10.1016/j.celrep.2019.06.056

Cited by 31 publications

(42 citation statements)

References 41 publications

(63 reference statements)

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“…4g). We still do not know if this finding can be generalized to other HPs endowed with paracrine activity 13 , but if so, may give new insights into how tissue morphogenesis and cell metabolism influence each other. Given the role of HPs expression in evolution, it is tempting to consider how such a mechanism may have contributed to link the second rise in atmospheric oxygen to the concomitant increase in metazoan complexity 38 .…”

Section: Resultsmentioning

confidence: 99%

“…Although first characterized as purely cell autonomous transcription factors 10 , HPs are also transferred between cells via non-conventional secretion and internalization routes, providing them with direct paracrine activity 11 . Intercellular transfer is a general property of HPs, and its efficiency is context-dependent 12,13 . Within recipient cells, transferred HPs may act not only as transcription factors but also on processes as diverse as translation, DNA repair, mitochondrial activity, and epigenetic modification 14 .…”

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confidence: 99%

“…Engrailed 2 intercellular transfer is asymmetrically regulated by H 2 O 2 . To evaluate the sensitivity of Engrailed trafficking to H 2 O 2 levels, we performed assays in HeLa cells, where this process has been best charaterized 13,21,23 . H 2 O 2 levels were fine-tuned with two strategies.…”

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confidence: 99%

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H2O2 and Engrailed 2 paracrine activity synergize to shape the zebrafish optic tectum

et al. 2020

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Although a physiological role for redox signaling is now clearly established, the processes sensitive to redox signaling remains to be identified. Ratiometric probes selective for H2O2 have revealed its complex spatiotemporal dynamics during neural development and adult regeneration and perturbations of H2O2 levels disturb cell plasticity and morphogenesis. Here we ask whether endogenous H2O2 could participate in the patterning of the embryo. We find that perturbations of endogenous H2O2 levels impact on the distribution of the Engrailed homeoprotein, a strong determinant of midbrain patterning. Engrailed 2 is secreted from cells with high H2O2 levels and taken up by cells with low H2O2 levels where it leads to increased H2O2 production, steering the directional spread of the Engrailed gradient. These results illustrate the interplay between protein signaling pathways and metabolic processes during morphogenetic events.

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Section: Resultsmentioning

confidence: 99%

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confidence: 99%

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H2O2 and Engrailed 2 paracrine activity synergize to shape the zebrafish optic tectum

et al. 2020

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“…The paracrine mode of action of homeoprotein is a direct consequence of their trafficking properties. First demonstrated with selected homeoproteins (Di Nardo et al, 2018), a recent study that now shows that intercellular trafficking is common to most if not all homeoproteins (Lee et al, 2019), suggests that paracrine functions might be a shared property within this protein family. Whether PIP 2 might act as a generic regulator of homeoprotein trafficking is an interesting possibility, also considering that PIP 2 levels are the target of multiple signalization pathways within the cell.…”

Section: Discussionmentioning

confidence: 98%

Bidirectional transfer of Engrailed homeoprotein across the plasma membrane requires PIP2

Amblard

Dupont

Alves

et al. 2020

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Statement: Deciphering the mechanism of homeoprotein intercellular trafficking AbstractHomeoproteins are a class of transcription factors sharing the unexpected property of intercellular trafficking. It confers to homeoproteins a paracrine mode of action, shown to exert a wide range of physiological functions, during development and in the adult. Internalization and secretion, the two steps of intercellular transfer, rely on unconventional mechanisms but the cellular mechanisms at stake still need to be fully characterized. Thanks to the design of new quantitative and sensitive assays dedicated to the study of homeoprotein transfer in cell culture, we demonstrate a core role of the phosphoinositides PIP 2 together with cholesterol in the 2 translocation of Engrailed2 (EN2) homeoprotein across the plasma membrane. Both secretion and internalization are regulated according to PIP 2 levels, challenged by drug or enzymatic treatments. In addition, EN2 specifically interacts with PIP 2 and the reduced affinity of a paracrine deficient mutant of EN2 supports a role of PIP 2 in homeoprotein physiological function. We propose that the two ways plasma membrane translocation steps accounting for homeoprotein secretion and internalization respectively are parts of a common process.

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“…While we will describe below current knowledge of the internalization and secretion mechanisms, it must be emphasized that the homeodomain, which is a very highly conserved structure (1,4,(7)(8)(9), is necessary and sufficient for transfer both in plants and in animals (10)(11)(12). This is probably why almost all homeoproteins tested so far (~150) have demonstrated intercellular passage, both in vitro and in vivo (13).…”

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confidence: 99%

Homeoprotein transduction in neurodevelopment and physiopathology

2020

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Homeoproteins were originally identified for embryonic cell–autonomous transcription activity, but they also have non–cell-autonomous activity owing to transfer between cells. This Review discusses transfer mechanisms and focuses on some established functions, such as neurodevelopmental regulation of axon guidance, and postnatal critical periods of brain plasticity that affect sensory processing and cognition. Homeoproteins are present across all eukaryotes, and intercellular transfer occurs in plants and animals. Proposed functions have evolutionary relevance, such as morphogenetic activity and sexual exchange during the mating of unicellular eukaryotes, while others have physiopathological relevance, such as regulation of mood and cognition by influencing brain compartmentalization, connectivity, and plasticity. There are more than 250 known homeoproteins with conserved transfer domains, suggesting that this is a common mode of signal transduction but with many undiscovered functions.

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Global Analysis of Intercellular Homeodomain Protein Transfer

Abstract: Graphical AbstractHighlights d Intercellular transfer is a general feature of homeodomain proteins (HPs) d HP secretion is a cell-context-sensitive event d Hydrophobic residues outside of the homeodomain support the secretion of HP

Cited by 31 publications

References 41 publications

H2O2 and Engrailed 2 paracrine activity synergize to shape the zebrafish optic tectum

H2O2 and Engrailed 2 paracrine activity synergize to shape the zebrafish optic tectum

Bidirectional transfer of Engrailed homeoprotein across the plasma membrane requires PIP2

Homeoprotein transduction in neurodevelopment and physiopathology

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