Novel role of PKR in inflammasome activation and HMGB1 release

By Ben Lu, Takahisa Nakamura, Karen E. Inouye, Jianhua Li, Yiting Tang, P. Lundbäck, S. Valdés-Ferrer, P. Olofsson, T. Kalb, J. Roth and 10 more. Nature, 2012

769 citations recorded by the source corpus.

The inflammasome regulates the release of caspase activation-dependent cytokines, including interleukin (IL)-1β, IL-18 and high-mobility group box 1 (HMGB1). By studying HMGB1 release mechanisms, here we identify a role for double-stranded RNA-dependent protein kinase (PKR, also known as EIF2AK2) in inflammasome activation. Exposure of macrophages to inflammasome agonists induced PKR autophosphorylation. PKR inactivation by genetic deletion or pharmacological inhibition severely impaired inflammasome activation in response to double-stranded RNA, ATP, monosodium urate, adjuvant aluminium, rotenone, live Escherichia coli, anthrax lethal toxin, DNA transfection and Salmonella typhimurium infection. PKR deficiency significantly inhibited the secretion of IL-1β, IL-18 and HMGB1 in E. coli-induced peritonitis. PKR physically interacts with several inflammasome components, including NOD-like receptor (NLR) family pyrin domain-containing 3 (NLRP3), NLRP1, NLR family CARD domain-containing protein 4 (NLRC4), absent in melanoma 2 (AIM2), and broadly regulates inflammasome activation. PKR autophosphorylation in a cell-free system with recombinant NLRP3, apoptosis-associated speck-like protein containing a CARD (ASC, also known as PYCARD) and pro-caspase-1 reconstitutes inflammasome activity. These results show a crucial role for PKR in inflammasome activation, and indicate that it should be possible to pharmacologically target this molecule to treat inflammation.

Subfields: Clinical Biochemistry, Molecular Biology, Physiology

View Paper: https://www.semanticscholar.org/paper/4c80c58961c768849b7448970f165e9632ba15bd

How researchers see this paper

The researchers whose trusted networks rank it highest, strongest advocate first. Every researcher gets a different order.

In Clinical Biochemistry

1. C. Deutschman
2. Kevin J. Tracey

In Molecular Biology

1. M. Lamkanfi
2. Yuan He
3. G. Núñez
4. V. Dixit
5. C. Deutschman
6. H. Hara
7. Rongbin Zhou
8. N. Rosenblatt-Velin

In Physiology

1. G. Núñez
2. Peter Walter
3. M. Lamkanfi
4. V. Dixit
5. L. Liaudet
6. Kevin J. Tracey
7. C. A. Dinarello

Citations in the corpus

• Identification of a selective and direct NLRP3 inhibitor to treat inflammatory disorders (2017, background): “First, IL-1β production is not the only biological effect of NLRP3 inflammasome activation; the pyroptosis or other proinflammatory factors, such as IL-18 and HMGB1, might also are involved in the pathogenesis of diseases (Lu et al., 2012; Nowarski et al., 2015).”
• ER stress-induced cell death mechanisms. (2013, background): “[81] reported that PKR broadly regulates inflammasome activation by phosphorylating members of the NLR (Nucleotide binding, Leucine rich repeat Receptors), including NLRP3 (NLR family pyrin domain-containing 3), NLRP1, and NLRC4 (NLR family CARD domain-containing protein 4).”
• The NLRP3 Inflammasome: An Overview of Mechanisms of Activation and Regulation (2019, background): “reported that PKR regulates the activation of several inflammasomes, including the NLRP1, NLRP3, NLRC4, and AIM2 inflammasomes [163].”
• The integrated stress response: From mechanism to disease (2020, background): “Activated PKR also links to inflammasome activation through direct coassemblywithNODlike receptors (205).”
• Mechanism and regulation of NLRP3 inflammasome activation (2016, background): “To date, five PRRs (NLRP1, NLRP3, NLRC4, Pyrin, and AIM2) have been shown to form inflammasomes [6,7].”
• The role of oxidative stress during inflammatory processes (2013, background): “This promotes the accumulation of HMGB1 within the cytoplasm, by preventing its nuclear re-entry, resulting in the active release of HMGB1 by monocytes/macrophages, particularly under conditions of inflammasome activation (Lu et  al., 2012).”
• Sepsis: current dogma and new perspectives. (2014, background): “A key step in inflammasome assembly is the phosphorylation of double-stranded RNA-dependent protein kinase (PKR, also known as EIF2AK2), a process triggered by DAMPs and pathogen-associated molecular patterns (PAMPs) (Lu et al., 2012).”
• Mechanisms and functions of inflammasomes. (2014, background): “There is disagreement too as to whether PKR (Lu et al., 2012), TXNIP (Zhou et al., 2010), and MAVS (Subramanian et al., 2013) have important roles in the Nlrp3 pathway (Ermler et al., 2014; He et al., 2013; Masters et al., 2010; Muñ oz-Planillo et al., 2013).”