BECN2 (beclin 2) Negatively Regulates Inflammasome Sensors Through ATG9A-Dependent but ATG16L1- and LC3-Independent Non-Canonical Autophagy

Guangtong Deng; Chaoran Li; Lang Chen; Changsheng Xing; Chuntang Fu; Chen Qian; Xin Liu; Helen Y Wang; Motao Zhu; Rong-Fu Wang

doi:10.1080/15548627.2021.1934270

BECN2 (beclin 2) Negatively Regulates Inflammasome Sensors Through ATG9A-Dependent but ATG16L1- and LC3-Independent Non-Canonical Autophagy

Autophagy. 2022 Feb;18(2):340-356. doi: 10.1080/15548627.2021.1934270. Epub 2021 Jun 21.

Authors

Guangtong Deng^{1

2}, Chaoran Li^{1

3}, Lang Chen^{1

2}, Changsheng Xing^{1

4}, Chuntang Fu^{1

4}, Chen Qian^{1

4}, Xin Liu^{1

4}, Helen Y Wang^{1

4}, Motao Zhu^{1

4}, Rong-Fu Wang^{1

4

5

6}

Affiliations

¹ Center for Inflammation and Epigenetics, Houston Methodist Research Institute, Houston, TX, USA.
² Department of Dermatology, Xiangya Hospital, Central South University, Changsha, Hunan, China.
³ Department of Ophthalmology, The Second Xiangya Hospital, Central South University, Changsha, Hunan, China.
⁴ Department of Medicine, Keck School of Medicine, University of Southern California, Los Angeles, CA, USA.
⁵ Norris Comprehensive Cancer Center, Keck School of Medicine, University of Southern California, Los Angeles, CA, USA.
⁶ Department of Pediatrics, Children's Hospital Los Angeles, Keck School of Medicine, University of Southern California, Los Angeles, CA, USA.

Abstract

Macroautophagy/autophagy-related proteins regulate infectious and inflammatory diseases in autophagy-dependent or -independent manner. However, the role of a newly identified mammalian-specific autophagy protein-BECN2 (beclin 2) in innate immune regulation is largely unknown. Here we showed that loss of BECN2 enhanced the activities of NLRP3, AIM2, NLRP1, and NLRC4 inflammasomes upon ligand stimulations. Mechanistically, BECN2 interacted with inflammasome sensors and mediated their degradation through a ULK1- and ATG9A-dependent, but BECN1-WIPI2-ATG16L1-LC3-independent, non-canonical autophagic pathway. BECN2 recruited inflammasome sensors on ATG9A⁺ vesicles to form a complex (BECN2-ATG9A-sensors) upon ULK1 activation. Three soluble NSF attachment protein receptor (SNARE) proteins (SEC22A, STX5, and STX6) were further shown to mediate the BECN2-ATG9A-dependent inflammasome sensor degradation. Loss of BECN2 promoted alum-induced peritonitis, which could be rescued by the ablation of CASP1 in Becn2-deficient mice. Hence, BECN2 negatively regulated inflammasome activation to control inflammation, serving as a potential therapeutic target for the treatment of infectious and inflammatory diseases.Abbreviations: AIM2: absent in melanoma 2; ATG: autophagy related; BECN1: beclin 1; BMDC: bone marrow-derived dendritic cells; BMDM: bone marrow-derived macrophages; CASP1: caspase 1; CQ: chloroquine; gMDSC: granulocytic myeloid-derived suppressor cells; IL: interleukin; LPS: lipopolysaccharide; MAP1LC3B: microtubule associated protein 1 light chain 3 beta; mMDSC: monocytic myeloid-derived suppressor cells; NLRC4: NLR family CARD domain containing 4; NLRP1: NLR family pyrin domain containing 1; NLRP3: NLR family pyrin domain containing 3; PECs: peritoneal exudate cells; PYCARD/ASC: apoptosis-associated speck-like protein containing a caspase activation and recruitment domain; SNAREs: soluble NSF attachment protein receptors; STX5: syntaxin 5; STX6: syntaxin 6; ULK1: unc-51 like autophagy activating kinase 1; WIPI: WD repeat domain, phosphoinositide interacting.

Keywords: ATG9A; Alum-induced peritonitis; BECN2; STX5-STX6-SEC22A-mediated membrane fusion; inflammasome; non-canonical autophagy.

Publication types

Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't

MeSH terms

Animals
Autophagy* / physiology
Autophagy-Related Proteins
Beclin-1
Caspase 1 / metabolism
Inflammasomes* / metabolism
Interleukin-1beta
Intracellular Signaling Peptides and Proteins
Lipopolysaccharides / pharmacology
Mammals / metabolism
Membrane Proteins
Mice
NLR Family, Pyrin Domain-Containing 3 Protein / metabolism
Qa-SNARE Proteins
Vesicular Transport Proteins

Substances

Atg16l1 protein, mouse
Atg9A protein, mouse
Autophagy-Related Proteins
Beclin-1
Becn2 protein, mouse
Inflammasomes
Interleukin-1beta
Intracellular Signaling Peptides and Proteins
Lipopolysaccharides
Membrane Proteins
NLR Family, Pyrin Domain-Containing 3 Protein
Qa-SNARE Proteins
Vesicular Transport Proteins
Caspase 1

Abstract

Publication types

MeSH terms

Substances

Grants and funding