Selective autophagy of RIPosomes maintains innate immune homeostasis during bacterial infection

Subhash Mehto; Kautilya Kumar Jena; Rina Yadav; Swatismita Priyadarsini; Pallavi Samal; Sivaram Krishna; Kollori Dhar; Ashish Jain; Nishant Ranjan Chauhan; Krushna C. Murmu; Ramyasingh Bal; Rinku Sahu; Pundrik Jaiswal; Bhabani Sankar Sahoo; Srinivas Patnaik; Thomas A. Kufer; Tor Erik Rusten; Swati Chauhan; Punit Prasad; Santosh Chauhan

doi:10.15252/embj.2022111289

Selective autophagy of RIPosomes maintains innate immune homeostasis during bacterial infection

Subhash Mehto, Kautilya Kumar Jena, Rina Yadav, Swatismita Priyadarsini, Pallavi Samal, Sivaram Krishna, Kollori Dhar, Ashish Jain, Nishant Ranjan Chauhan, Krushna C. Murmu, Ramyasingh Bal, Rinku Sahu, Pundrik Jaiswal, Bhabani Sankar Sahoo, Srinivas Patnaik, Thomas A. Kufer, Tor Erik Rusten, Swati Chauhan, Punit Prasad, Santosh Chauhan

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

Abstract

The NOD1/2-RIPK2 is a key cytosolic signaling complex that activates NF-κB pro-inflammatory response against invading pathogens. However, uncontrolled NF-κB signaling can cause tissue damage leading to chronic diseases. The mechanisms by which the NODs-RIPK2-NF-κB innate immune axis is activated and resolved remain poorly understood. Here, we demonstrate that bacterial infection induces the formation of endogenous RIPK2 oligomers (RIPosomes) that are self-assembling entities that coat the bacteria to induce NF-κB response. Next, we show that autophagy proteins IRGM and p62/SQSTM1 physically interact with NOD1/2, RIPK2 and RIPosomes to promote their selective autophagy and limit NF-κB activation. IRGM suppresses RIPK2-dependent pro-inflammatory programs induced by Shigella and Salmonella. Consistently, the therapeutic inhibition of RIPK2 ameliorates Shigella infection- and DSS-induced gut inflammation in Irgm1 KO mice. This study identifies a unique mechanism where the innate immune proteins and autophagy machinery are recruited together to the bacteria for defense as well as for maintaining immune homeostasis.

Original language	English (US)
Article number	e111289
Journal	EMBO Journal
Volume	41
Issue number	23
DOIs	https://doi.org/10.15252/embj.2022111289
State	Published - Dec 1 2022
Externally published	Yes

Keywords

Irgm1
NOD1/2-RIPK2-NF-κB
RIPosomes
autophagy
inflammation

ASJC Scopus subject areas

General Neuroscience
Molecular Biology
General Biochemistry, Genetics and Molecular Biology
General Immunology and Microbiology

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Mehto, S., Jena, K. K., Yadav, R., Priyadarsini, S., Samal, P., Krishna, S., Dhar, K., Jain, A., Chauhan, N. R., Murmu, K. C., Bal, R., Sahu, R., Jaiswal, P., Sahoo, B. S., Patnaik, S., Kufer, T. A., Rusten, T. E., Chauhan, S., Prasad, P., & Chauhan, S. (2022). Selective autophagy of RIPosomes maintains innate immune homeostasis during bacterial infection. EMBO Journal, 41(23), Article e111289. https://doi.org/10.15252/embj.2022111289

Mehto, S, Jena, KK, Yadav, R, Priyadarsini, S, Samal, P, Krishna, S, Dhar, K, Jain, A, Chauhan, NR, Murmu, KC, Bal, R, Sahu, R, Jaiswal, P, Sahoo, BS, Patnaik, S, Kufer, TA, Rusten, TE, Chauhan, S, Prasad, P & Chauhan, S 2022, 'Selective autophagy of RIPosomes maintains innate immune homeostasis during bacterial infection', EMBO Journal, vol. 41, no. 23, e111289. https://doi.org/10.15252/embj.2022111289

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title = "Selective autophagy of RIPosomes maintains innate immune homeostasis during bacterial infection",

abstract = "The NOD1/2-RIPK2 is a key cytosolic signaling complex that activates NF-κB pro-inflammatory response against invading pathogens. However, uncontrolled NF-κB signaling can cause tissue damage leading to chronic diseases. The mechanisms by which the NODs-RIPK2-NF-κB innate immune axis is activated and resolved remain poorly understood. Here, we demonstrate that bacterial infection induces the formation of endogenous RIPK2 oligomers (RIPosomes) that are self-assembling entities that coat the bacteria to induce NF-κB response. Next, we show that autophagy proteins IRGM and p62/SQSTM1 physically interact with NOD1/2, RIPK2 and RIPosomes to promote their selective autophagy and limit NF-κB activation. IRGM suppresses RIPK2-dependent pro-inflammatory programs induced by Shigella and Salmonella. Consistently, the therapeutic inhibition of RIPK2 ameliorates Shigella infection- and DSS-induced gut inflammation in Irgm1 KO mice. This study identifies a unique mechanism where the innate immune proteins and autophagy machinery are recruited together to the bacteria for defense as well as for maintaining immune homeostasis.",

keywords = "Irgm1, NOD1/2-RIPK2-NF-κB, RIPosomes, autophagy, inflammation",

author = "Subhash Mehto and Jena, {Kautilya Kumar} and Rina Yadav and Swatismita Priyadarsini and Pallavi Samal and Sivaram Krishna and Kollori Dhar and Ashish Jain and Chauhan, {Nishant Ranjan} and Murmu, {Krushna C.} and Ramyasingh Bal and Rinku Sahu and Pundrik Jaiswal and Sahoo, {Bhabani Sankar} and Srinivas Patnaik and Kufer, {Thomas A.} and Rusten, {Tor Erik} and Swati Chauhan and Punit Prasad and Santosh Chauhan",

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year = "2022",

month = dec,

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doi = "10.15252/embj.2022111289",

language = "English (US)",

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T1 - Selective autophagy of RIPosomes maintains innate immune homeostasis during bacterial infection

AU - Mehto, Subhash

AU - Jena, Kautilya Kumar

AU - Yadav, Rina

AU - Priyadarsini, Swatismita

AU - Samal, Pallavi

AU - Krishna, Sivaram

AU - Dhar, Kollori

AU - Jain, Ashish

AU - Chauhan, Nishant Ranjan

AU - Murmu, Krushna C.

AU - Bal, Ramyasingh

AU - Sahu, Rinku

AU - Jaiswal, Pundrik

AU - Sahoo, Bhabani Sankar

AU - Patnaik, Srinivas

AU - Kufer, Thomas A.

AU - Rusten, Tor Erik

AU - Chauhan, Swati

AU - Prasad, Punit

AU - Chauhan, Santosh

PY - 2022/12/1

Y1 - 2022/12/1

N2 - The NOD1/2-RIPK2 is a key cytosolic signaling complex that activates NF-κB pro-inflammatory response against invading pathogens. However, uncontrolled NF-κB signaling can cause tissue damage leading to chronic diseases. The mechanisms by which the NODs-RIPK2-NF-κB innate immune axis is activated and resolved remain poorly understood. Here, we demonstrate that bacterial infection induces the formation of endogenous RIPK2 oligomers (RIPosomes) that are self-assembling entities that coat the bacteria to induce NF-κB response. Next, we show that autophagy proteins IRGM and p62/SQSTM1 physically interact with NOD1/2, RIPK2 and RIPosomes to promote their selective autophagy and limit NF-κB activation. IRGM suppresses RIPK2-dependent pro-inflammatory programs induced by Shigella and Salmonella. Consistently, the therapeutic inhibition of RIPK2 ameliorates Shigella infection- and DSS-induced gut inflammation in Irgm1 KO mice. This study identifies a unique mechanism where the innate immune proteins and autophagy machinery are recruited together to the bacteria for defense as well as for maintaining immune homeostasis.

AB - The NOD1/2-RIPK2 is a key cytosolic signaling complex that activates NF-κB pro-inflammatory response against invading pathogens. However, uncontrolled NF-κB signaling can cause tissue damage leading to chronic diseases. The mechanisms by which the NODs-RIPK2-NF-κB innate immune axis is activated and resolved remain poorly understood. Here, we demonstrate that bacterial infection induces the formation of endogenous RIPK2 oligomers (RIPosomes) that are self-assembling entities that coat the bacteria to induce NF-κB response. Next, we show that autophagy proteins IRGM and p62/SQSTM1 physically interact with NOD1/2, RIPK2 and RIPosomes to promote their selective autophagy and limit NF-κB activation. IRGM suppresses RIPK2-dependent pro-inflammatory programs induced by Shigella and Salmonella. Consistently, the therapeutic inhibition of RIPK2 ameliorates Shigella infection- and DSS-induced gut inflammation in Irgm1 KO mice. This study identifies a unique mechanism where the innate immune proteins and autophagy machinery are recruited together to the bacteria for defense as well as for maintaining immune homeostasis.

KW - Irgm1

KW - NOD1/2-RIPK2-NF-κB

KW - RIPosomes

KW - autophagy

KW - inflammation

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JO - EMBO Journal

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ER -

Selective autophagy of RIPosomes maintains innate immune homeostasis during bacterial infection

Abstract

Keywords

ASJC Scopus subject areas

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