The adapter MAVS promotes NLRP3 mitochondrial localization and inflammasome activation

By N. Subramanian, K. Natarajan, M. Clatworthy, Ze Wang, Ronald N. Germain. Cell, 2013

658 citations recorded by the source corpus.

Summary NLRP3 is a key component of the macromolecular signaling complex called the inflammasome that promotes caspase 1-dependent production of IL-1β. The adapter ASC is necessary for NLRP3-dependent inflammasome function, but it is not known if ASC is a sufficient partner, and whether inflammasome formation occurs in the cytosol or in association with mitochondria is controversial. Here we show that the mitochondria-associated adapter molecule, MAVS, is required for optimal NLRP3 inflammasome activity. MAVS mediates recruitment of NLRP3 to mitochondria, promoting production of IL-1β and the pathophysiologic activity of the NLRP3 inflammasome in vivo. Our data support a more complex model of NLRP3 inflammasome activation than previously appreciated, with at least two adapters required for maximal function. Since MAVS is a mitochondria-associated molecule previously considered to be uniquely involved in type 1 interferon production, these findings also reveal unexpected polygamous involvement of PYD/CARD domain-containing adapters in innate immune signaling events.

Subfields: Immunology, Molecular Biology

View Paper: https://www.semanticscholar.org/paper/b52baaf2c792ab874af6e4dc35d0b7e8003b3c8b

How researchers see this paper

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

In Immunology

1. M. Lamkanfi
2. V. Dixit
3. G. Núñez
4. B. Beutler
5. H. Hara
6. R. Ulevitch
7. F. Sutterwala
8. Yuan He

In Molecular Biology

1. M. Lamkanfi
2. Yuan He
3. G. Núñez
4. H. Hara
5. V. Dixit
6. F. Sutterwala
7. B. Beutler
8. Eric I. Elliott

Citations in the corpus

• NLRP3 activation and mitosis are mutually exclusive events coordinated by NEK7, a new inflammasome component (2015, positive): “Lys NLRP3 ASC WT K64M WT (1) Nek7 +/+ (GFP) (2) Nek7 (GFP) (3) Nek7 (GFP + NEK7) (4) Nek7 (GFP + NEK7(K64M))”
• Mechanism and regulation of NLRP3 inflammasome activation (2016, background): “However, the role of MAVS in NLRP3 inflammasome activation remains controversial [19,53].”
• Initiation and perpetuation of NLRP3 inflammasome activation and assembly (2015, background): “ASC specks form at the site of initiation of inflammasome formation as NLRP3-dependent ASC aggregates localize to mitochondria (138).”
• Reactive oxygen species and mitochondria: A nexus of cellular homeostasis (2015, background): “ROS produced downstream of NLRP3 stimuli cause dissociation of Nrf2 from Keap1 and translocation to the cytosol, where it associates with ASC aggregates [128].”
• 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).”
• Redox Regulation of NLRP3 Inflammasomes: ROS as Trigger or Effector? (2015, neutral): “to mediate the relocalization and association of NLRP3 to mitochondria (120).”
• The NLRP3 Inflammasome: An Overview of Mechanisms of Activation and Regulation (2019, background): “MAVS physically interacts with NLRP3 and it is required for NLRP3 inflammasome activation induced by soluble stimuli, such as ATP, nigericin, and poly (I:C), but not by particulate stimuli, such as silica, alum, and MSU [101,102].”