The Role of HDAC6 in Autophagy and NLRP3 Inflammasome

Abstract

Autophagy fights against harmful stimuli and degrades cytosolic macromolecules, organelles, and intracellular pathogens. Autophagy dysfunction is associated with many diseases, including infectious and inflammatory diseases. Recent studies have identified the critical role of the NACHT, LRR, and PYD domain-containing protein 3 (NLRP3) inflammasomes activation in the innate immune system, which mediates the secretion of proinflammatory cytokines IL-1β/IL-18 and cleaves Gasdermin D to induce pyroptosis in response to pathogenic and sterile stimuli. Accumulating evidence has highlighted the crosstalk between autophagy and NLRP3 inflammasome in multifaceted ways to influence host defense and inflammation. However, the underlying mechanisms require further clarification. Histone deacetylase 6 (HDAC6) is a class IIb deacetylase among the 18 mammalian HDACs, which mainly localizes in the cytoplasm. It is involved in two functional deacetylase domains and a ubiquitin-binding zinc finger domain (ZnF-BUZ). Due to its unique structure, HDAC6 regulates various physiological processes, including autophagy and NLRP3 inflammasome, and may play a role in the crosstalk between them. In this review, we provide insight into the mechanisms by which HDAC6 regulates autophagy and NLRP3 inflammasome and we explored the possibility and challenges of HDAC6 in the crosstalk between autophagy and NLRP3 inflammasome. Finally, we discuss HDAC6 inhibitors as a potential therapeutic approach targeting either autophagy or NLRP3 inflammasome as an anti-inflammatory strategy, although further clarification is required regarding their crosstalk.

Keywords: HDAC6; NLRP3 inflammasome; autophagy; inflammation; post-translational modification.

Figure 1

The role of HDAC6 in autophagy. (A) The role of HDAC6 in PTM of autophagy-related transcription factors. HDAC6 deacetylates transcription factors, TFEB and FOXO1, to reduce their transcriptional activity and inhibit autophagy. (B) HDAC6 promotes the autophagic degradation of aggresome in various ways. Left: HDAC6 interacts with the microtubule motor protein dynein to escort the ubiquitinated misfolded protein or ubiquitinated damaged mitochondria to form the aggresome, to transport the lysosome for the degardaion of aggresome, and to deliver LC3-II (the purple point) to promote the formation of the autophagosome containing aggresome. Right: HDAC6 deacetylates LC3-II to promote the formation of the autophagosome. (C) HDAC6 plays various roles in the regulation of autophagy via deacetylating α-tubulin and cortactin (positive and negative roles are marked with red and green respectively). Top-left: HDAC6 deacetylates microtubules to block the ER–Mit contact where autophagosome generates. Top-right: HDAC6 suppresses the transport of autophagosomes through deacetylating and reducing the stability of the microtubules. Bottom: HDAC6 blocks the fusion of the autophagosome that contains the misfolded protein or mitochondria and the lysosome by deacetylating cortactin. HDAC6, Histone deacetylase 6; TF, Transcription factor; PTM, Post-translational modifications; AC, Acetylation; FOXO1, Forkhead Box 1; TFEB, Transcription factor EB; MTOC, Microtubule-organizing center; LC3, Microtubule-associated protein 1 light chain 3; ER, Endoplasmic Reticulum; Mit, Mitochondria.

Figure 2

The role of HDAC6 in NLRP3 inflammasome. (A) In the priming of NLRP3 inflammasome, HDAC6 promotes NF-κB to enhance the transcription of NLRP3, pro-IL-1β and pro-IL-18. HDAC6 promotes NF-κB in a number of mechanisms. (1) TLR4 senses PAMPs and recruits the downstream adapter proteins MyD88. HDAC6 interacts with MyD88 to enhance the activation of NF-κB. (2) HDAC6 deacetylates microtubules to promote the activity of NF-κB. (3) HDAC6 elevates the expression of NOX2, the component of NADPH oxidase, to promote the level of ROS which upregulates NF-κB activity. (4) HDAC6 directly deacetylates NF-κB. Then, NF-κB upregulates the transcription of NLRP3, pro-IL-1β, and pro-IL-18. (B) The role of HDAC6 in the activation and PTM of NLRP3 inflammasome includes a variety of signaling mechanisms (positive and negative roles are marked with red and green respectively). HDAC6 regulates the activation of NLRP3 inflammasome in different ways. (1) HDAC6 suppresses the activity of Prx II via deacetylation and increase the level of ROS which is vital for the activation of NLRP3 inflammasome. (2) HDAC6 promotes the activation of NLRP3 inflammasome via suppressing F-actin, a negative factor of NLRP3 assembly. (3) HDAC6 enhances the expression of DDX3X. And DDX3X facilitates NLRP3 assembly. In addition, HDAC6 plays both the negative and positive roles in the PTM of NLRP3 inflammasome. The negative one: HDAC6 interacts with ubquitinated NLRP3 protein directly to prevents the activation of NLRP3 inflammasome. The positive one: In an aggresome-like way, HDAC6 works as a dynein adapter to facilitate retrograde transport of NLRP3 inflammasome for activation. Finally, NLRP3 inflammasome releases active caspase-1, which can promote pro-IL-1β/IL-18 to IL-1β/IL-18 and cleave GSDMD to induce pyroptosis. HDAC6, Histone deacetylase 6; NF-κB, Nuclear factor-kappaB; NLRP3, NACHT, LRR, and PYD domains-containing protein 3; Pro-IL-1β, Pro-interleukin-1β; Pro-IL-18, Pro-interleukin-18; PAMPs, Pathogen-associated molecular patterns; TLR4, Toll-like-receptor 4; MyD88, Myeloid differentiation primary response protein 88; AC, Acetylation; MT, microtubule; NADPH, nicotinamide adenine dinucleotide phosphate; NOX2, NADPH oxidase 2; ROS, Reactive oxygen species; Prx II, Peroxiredoxin II; DDX3X, DEAD-Box Helicase 3 X-Linked; F-actin, Filamentous actin; GSDMD, Gasdermin D.

Figure 3

The possible role of HDAC6 in the crosstalk between autophagy and NLRP3 inflammasome. (A) The possible role of HDAC6 in the autophagic degradation of the component of NLRP3 inflammasomes and endogenous inflammasome activators. As a source of endogenous inflammasome activators, damaged mitochondrion promotes the activation of NLRP3 inflammasome. Both the damaged mitochondrion and the component of NLRP3 inflammasome can be limited by autophagy. HDAC6 may promote the mitophagy and then inhibit the activation of NLRP3 inflammasome indirectly. Moreover, it is possible that the HDAC6 upregulate or downregulate autophagy to affect NLRP3 inflammasome. (B) The possible role of HDAC6 in the regulation of autophagy by NLRP3 inflammasome. HDAC6 plays a dual role in the activation of NLRP3 inflammasome, which release the caspase-1. Caspase-1 inhibits the autophagic degradation of the damaged mitochondrion or the component of NLRP3 inflammasome. Hence, HDAC6 may regulate autophagy via the activation of NLRP3 inflammasome. HDAC6, Histone deacetylase 6; NLRP3, NACHT, LRR, and PYD domain-containing protein 3.