Cellular delivery and photochemical release of a caged inositol-pyrophosphate induces PH-domain translocation in cellulo

Igor Pavlovic; Divyeshsinh T. Thakor; Jessica R. Vargas; Colin J. McKinlay; Sebastian Hauke; Philipp Anstaett; Rafael C. Camunã; Laurent Bigler; Gilles Gasser; Carsten Schultz; Paul A. Wender; Henning J. Jessen

doi:10.1038/ncomms10622

Cellular delivery and photochemical release of a caged inositol-pyrophosphate induces PH-domain translocation in cellulo

Igor Pavlovic
, Divyeshsinh T. Thakor
, Jessica R. Vargas
, Colin J. McKinlay
, Sebastian Hauke
, Philipp Anstaett
, Rafael C. Camunã
, Laurent Bigler
, Gilles Gasser
, Carsten Schultz
, Paul A. Wender
, Henning J. Jessen

Research output: Contribution to journal › Article › peer-review

84 Scopus citations

Abstract

Inositol pyrophosphates, such as diphospho-myo-inositol pentakisphosphates (InsP₇), are an important family of signalling molecules, implicated in many cellular processes and therapeutic indications including insulin secretion, glucose homeostasis and weight gain. To understand their cellular functions, chemical tools such as photocaged analogues for their real-time modulation in cells are required. Here we describe a concise, modular synthesis of InsP₇ and caged InsP₇. The caged molecule is stable and releases InsP₇ only on irradiation. While photocaged InsP₇ does not enter cells, its cellular uptake is achieved using nanoparticles formed by association with a guanidinium-rich molecular transporter. This novel synthesis and unprecedented polyphosphate delivery strategy enable the first studies required to understand InsP₇ signalling in cells with controlled spatiotemporal resolution. It is shown herein that cytoplasmic photouncaging of InsP₇ leads to translocation of the PH-domain of Akt, an important signalling-node kinase involved in glucose homeostasis, from the membrane into the cytoplasm.

Original language	English (US)
Article number	10622
Journal	Nature communications
Volume	7
DOIs	https://doi.org/10.1038/ncomms10622
State	Published - Feb 4 2016
Externally published	Yes

Funding

Imaging was performed with support of the Center for Microscopy and Image Analysis at UZH and the Stanford Shared FACS Facility. We thank Professors Jay Siegel, John Robinson, Adolfo Saiardi, Robert Waymouth, Chris Contag, Lynette Cegelski, Dr. Vanessa Pierroz, Dr. Riccardo Rubbiani and Dr. Vibor Laketa for discussions, materials and procedures. This work was supported by The Swiss National Science Foundation (PP00P2_157607 to H.J.J. and PP00P2_133568 & PP00P2_157545 to G.G.), the National Institutes of Health (NIH-CA031841, NIH-S10RR027431-01 and NIH-CA031845 to P.A.W.), and the Deutsche Forschungsgemeinschaft (DFG, TRR83 to C.S.). Fellowships: National Science Foundation and the Stanford Center for Molecular Analysis and Design.

Funders	Funder number
Author National Institutes of Health National Institutes of Health National Institutes of Health National Institutes of Health The Bev Hartig Huntington's Disease Foundation National Institutes of Health	NIH-S10RR027431-01, NIH-CA031841
National Institute of Health-National Cancer Institute	R01CA031845
Deutsche Forschungsgemeinschaft	TRR83
Schweizerischer Nationalfonds zur Förderung der Wissenschaftlichen Forschung	PP00P2_157607, PP00P2_157545, PP00P2_133568

ASJC Scopus subject areas

General Chemistry
General Biochemistry, Genetics and Molecular Biology
General
General Physics and Astronomy

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10.1038/ncomms10622

Cite this

Pavlovic, I., Thakor, D. T., Vargas, J. R., McKinlay, C. J., Hauke, S., Anstaett, P., Camunã, R. C., Bigler, L., Gasser, G., Schultz, C., Wender, P. A., & Jessen, H. J. (2016). Cellular delivery and photochemical release of a caged inositol-pyrophosphate induces PH-domain translocation in cellulo. Nature communications, 7, Article 10622. https://doi.org/10.1038/ncomms10622

@article{5e7d985238724266a270e11214687ee3,

title = "Cellular delivery and photochemical release of a caged inositol-pyrophosphate induces PH-domain translocation in cellulo",

abstract = "Inositol pyrophosphates, such as diphospho-myo-inositol pentakisphosphates (InsP7), are an important family of signalling molecules, implicated in many cellular processes and therapeutic indications including insulin secretion, glucose homeostasis and weight gain. To understand their cellular functions, chemical tools such as photocaged analogues for their real-time modulation in cells are required. Here we describe a concise, modular synthesis of InsP7 and caged InsP7. The caged molecule is stable and releases InsP7 only on irradiation. While photocaged InsP7 does not enter cells, its cellular uptake is achieved using nanoparticles formed by association with a guanidinium-rich molecular transporter. This novel synthesis and unprecedented polyphosphate delivery strategy enable the first studies required to understand InsP7 signalling in cells with controlled spatiotemporal resolution. It is shown herein that cytoplasmic photouncaging of InsP7 leads to translocation of the PH-domain of Akt, an important signalling-node kinase involved in glucose homeostasis, from the membrane into the cytoplasm.",

author = "Igor Pavlovic and Thakor, \{Divyeshsinh T.\} and Vargas, \{Jessica R.\} and McKinlay, \{Colin J.\} and Sebastian Hauke and Philipp Anstaett and Camun{\~a}, \{Rafael C.\} and Laurent Bigler and Gilles Gasser and Carsten Schultz and Wender, \{Paul A.\} and Jessen, \{Henning J.\}",

note = "Funding Information: Imaging was performed with support of the Center for Microscopy and Image Analysis at UZH and the Stanford Shared FACS Facility. We thank Professors Jay Siegel, John Robinson, Adolfo Saiardi, Robert Waymouth, Chris Contag, Lynette Cegelski, Dr. Vanessa Pierroz, Dr. Riccardo Rubbiani and Dr. Vibor Laketa for discussions, materials and procedures. This work was supported by The Swiss National Science Foundation (PP00P2\_157607 to H.J.J. and PP00P2\_133568 \& PP00P2\_157545 to G.G.), the National Institutes of Health (NIH-CA031841, NIH-S10RR027431-01 and NIH-CA031845 to P.A.W.), and the Deutsche Forschungsgemeinschaft (DFG, TRR83 to C.S.). Fellowships: National Science Foundation and the Stanford Center for Molecular Analysis and Design.",

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doi = "10.1038/ncomms10622",

language = "English (US)",

volume = "7",

journal = "Nature communications",

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T1 - Cellular delivery and photochemical release of a caged inositol-pyrophosphate induces PH-domain translocation in cellulo

AU - Pavlovic, Igor

AU - Thakor, Divyeshsinh T.

AU - Vargas, Jessica R.

AU - McKinlay, Colin J.

AU - Hauke, Sebastian

AU - Anstaett, Philipp

AU - Camunã, Rafael C.

AU - Bigler, Laurent

AU - Gasser, Gilles

AU - Schultz, Carsten

AU - Wender, Paul A.

AU - Jessen, Henning J.

N1 - Funding Information: Imaging was performed with support of the Center for Microscopy and Image Analysis at UZH and the Stanford Shared FACS Facility. We thank Professors Jay Siegel, John Robinson, Adolfo Saiardi, Robert Waymouth, Chris Contag, Lynette Cegelski, Dr. Vanessa Pierroz, Dr. Riccardo Rubbiani and Dr. Vibor Laketa for discussions, materials and procedures. This work was supported by The Swiss National Science Foundation (PP00P2_157607 to H.J.J. and PP00P2_133568 & PP00P2_157545 to G.G.), the National Institutes of Health (NIH-CA031841, NIH-S10RR027431-01 and NIH-CA031845 to P.A.W.), and the Deutsche Forschungsgemeinschaft (DFG, TRR83 to C.S.). Fellowships: National Science Foundation and the Stanford Center for Molecular Analysis and Design.

PY - 2016/2/4

Y1 - 2016/2/4

N2 - Inositol pyrophosphates, such as diphospho-myo-inositol pentakisphosphates (InsP7), are an important family of signalling molecules, implicated in many cellular processes and therapeutic indications including insulin secretion, glucose homeostasis and weight gain. To understand their cellular functions, chemical tools such as photocaged analogues for their real-time modulation in cells are required. Here we describe a concise, modular synthesis of InsP7 and caged InsP7. The caged molecule is stable and releases InsP7 only on irradiation. While photocaged InsP7 does not enter cells, its cellular uptake is achieved using nanoparticles formed by association with a guanidinium-rich molecular transporter. This novel synthesis and unprecedented polyphosphate delivery strategy enable the first studies required to understand InsP7 signalling in cells with controlled spatiotemporal resolution. It is shown herein that cytoplasmic photouncaging of InsP7 leads to translocation of the PH-domain of Akt, an important signalling-node kinase involved in glucose homeostasis, from the membrane into the cytoplasm.

AB - Inositol pyrophosphates, such as diphospho-myo-inositol pentakisphosphates (InsP7), are an important family of signalling molecules, implicated in many cellular processes and therapeutic indications including insulin secretion, glucose homeostasis and weight gain. To understand their cellular functions, chemical tools such as photocaged analogues for their real-time modulation in cells are required. Here we describe a concise, modular synthesis of InsP7 and caged InsP7. The caged molecule is stable and releases InsP7 only on irradiation. While photocaged InsP7 does not enter cells, its cellular uptake is achieved using nanoparticles formed by association with a guanidinium-rich molecular transporter. This novel synthesis and unprecedented polyphosphate delivery strategy enable the first studies required to understand InsP7 signalling in cells with controlled spatiotemporal resolution. It is shown herein that cytoplasmic photouncaging of InsP7 leads to translocation of the PH-domain of Akt, an important signalling-node kinase involved in glucose homeostasis, from the membrane into the cytoplasm.

UR - https://www.scopus.com/pages/publications/84957068217

UR - https://www.scopus.com/pages/publications/84957068217#tab=citedBy

U2 - 10.1038/ncomms10622

DO - 10.1038/ncomms10622

M3 - Article

C2 - 26842801

AN - SCOPUS:84957068217

SN - 2041-1723

VL - 7

JO - Nature communications

JF - Nature communications

M1 - 10622

ER -

Cellular delivery and photochemical release of a caged inositol-pyrophosphate induces PH-domain translocation in cellulo

Abstract

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