Regulation of pattern recognition receptor signaling by palmitoylation

Abstract

Pattern recognition receptors (PRRs), consisting of Toll-like receptors, RIG-I-like receptors, cytosolic DNA sensors, and NOD-like receptors, sense exogenous pathogenic molecules and endogenous damage signals to maintain physiological homeostasis. Upon activation, PRRs stimulate the sensitization of nuclear factor κB, mitogen-activated protein kinase, TANK-binding kinase 1-interferon (IFN) regulatory factor, and inflammasome signaling pathways to produce inflammatory factors and IFNs to activate Janus kinase/signal transducer and activator of transcription signaling pathways, resulting in anti-infection, antitumor, and other specific immune responses. Palmitoylation is a crucial type of post-translational modification that reversibly alters the localization, stability, and biological activity of target molecules. Here, we discuss the available knowledge on the biological roles and underlying mechanisms linked to protein palmitoylation in modulating PRRs and their downstream signaling pathways under physiological and pathological conditions. Moreover, recent advances in the use of palmitoylation as an attractive therapeutic target for disorders caused by the dysregulation of PRRs were summarized.

Keywords: Biological sciences; Immune response; Molecular biology.

Graphical abstract

Figure 1

Dynamic protein palmitoylation Palmitoylation is a reversible and dynamic posttranslational protein modification mediated by palmitoylases, such as ZDHHC1-9 and ZDHHC11-24, and depalmitoylases, including PPT1/2, APT1/2, ABHD10, ABHD16A, ABHD17 A/B/C, which attach to or remove palmitoyl groups from protein cysteine residues. ZDHHCs are self-palmitoylated first before transferring the palmitoyl group to substrates. Palmitoylation regulates protein membrane localization, stability, interaction, biological activity et al.

Figure 2

Regulation of TLRs and their adaptors mediated by protein palmitoylation TLR2, TLR5, TLR7, TLR9, and TLR10 can be directly palmitoylated. The palmitoylation site of TLR2 is Cys609. ZDHHC2, ZDHHC3, ZDHHC6, ZDHHC7, and ZDHHC15 are responsible for TLR2 palmitoylation. DJ-1 is palmitoylated at Cys46, Cys53, and Cys106. Palmitoylation of DJ-1 contributes to the abatement of TLR4 activation. Similarly, Lyn palmitoylation hurts TLR4 sensitization. TLR9 can be palmitoylated at Cys258 and Cys265. Palmitoylation of TLR9 is induced by ZDHHC3 but suppressed by PPT1. The palmitoylation sites of Myd88 are Cys113 and Cys274. FASN and CD36 mediated by fatty acids, including PA, induce palmitoylation of the adaptor protein Myd88. ZDHHC6 is the palmitoylase of Myd88. PA: palmitic acid.

Figure 3

Regulation of the RLR adaptor MAVS mediated by protein palmitoylation In the RLR signaling pathway, CPT1A interacts with ZDHHC4 to promote MAVS palmitoylation at Cys79. ZDHHC24 benefits MAVS palmitoylation, while APT2 depalmitoylates MAVS at Cys46 and Cys79. MAVS could also be palmitoylated by ZDHHC7 at Cys508. In addition, palmitoylation of Rac inhibits MAVS activation by inhibiting the interaction of TRIM31 with MAVS and recruiting cFLIPL and CASP8 to activate RIPK1 cleavage and subsequently inhibit MAVS.

Figure 4

Modulation of cytosolic DNA sensors and their adaptors induced by protein palmitoylation ZDHCC9 induces palmitoylation of the DNA sensor cGAS at Cys404/405 to promote its activation. LYPAL1 inhibits cGAS palmitoylation. ZHDHCC18 enhances cGAS palmitoylation at Cys474 to repress its activation. ASFV QP383R can inhibit cGAS by interacting with cGAS to enhance its palmitoylation. STING can be palmitoylated by FASN. STING is palmitoylated at Cys88 and Cys91. STING palmitoylation facilitates its packaging in CD63⁺ extracellular vesicles (EVs) and exocytosis. ZDHHC3, ZDHHC7, and ZDHHC15 induce palmitoylation of STING. EsxB inhibits palmitoylation of STING at Cys91 by disrupting the interaction between STING and ZDHHC3.

Figure 5

Modulation of RLRs induced by protein palmitoylation NLRP3 palmitoylation is induced by ZDHHC7 but suppressed by ABHD17A at Cys126. ZDHHC5 induces NLRP3 palmitoylation at Cys837/838. Palmitoylation of NLRP3 at Cys130 and Cys958 is regulated by ZDHHC1. Based on ZDHHC17, NLRP3 is palmitoylated at Cys419. Conversely, PPT1 suppresses NLRP3 palmitoylation. CD36 mediates the entry of phenylpyruvate into macrophages to inhibit PPT1 and promote NLRP3 palmitoylation. FASN enhances the palmitoylation of NLRP3 at Cys898. ZDHCC12 contributes to NLRP3 palmitoylation at Cys844 to inhibit its expression by improving NLRP3 degradation via the HSC70 and LAMP2A-associated autophagy-lysosomal pathways. In addition, ABHD8 can recruit ZDHHC12 to NLRP3 to enhance NLRP3 degradation. NOD1 is palmitoylated at Cys558, Cys567, and Cys952. NOD2 is palmitoylated at Cys395 and Cys1033. ZDHHC5 contributes to palmitoylation of both NOD1 and NOD2. Palmitoylation of NOD2 blocks its degradation via the SQSTM1-associated autophagy-lysosomal pathway. However, ABHD17 inhibits NOD2 protein stabilization by reducing NOD2 palmitoylation.

Figure 6

Control of the downstream NF-κB and MAPK signaling pathways of PRRs mediated by protein palmitoylation TLRs (without TLR3) are located on the membrane and endosomes can activate the adaptor protein Myd88 to activate the NF-κB and MAPK signaling pathways. Similar to TLRs, cytosolic DNA sensors, NLRs, and the components of RLRs, including NOD1 and NOD2, also could sensitize NF-κB signaling. During NF-κB signaling, p65, IκB-α, IκB-β, and IKK-β can be palmitoylated. The palmitoylation of CDC42 at Cys186 facilitates NF-κB signaling activation. TNFR1 palmitoylation at Cys248 inhibits NF-κB signaling. However, APT2 can suppress TNFR1 palmitoylation to promote signaling activation in NF-κB signaling. In addition, Myd88 palmitoylation mediated by the activation of CD36 with PA can sensitize NF-κB signaling. In MAPK signaling, ERK1, ERK2, JNK2, and JNK3 can be directly palmitoylated. Although it is unknown whether p38 MAPK proteins can be directly palmitoylated, the palmitoylation inhibitor 2-BP can inhibit p38 MAPK signaling activation. In addition, the palmitoylation site of ERK1 is Cys271, and ERK2 palmitoylation site is Cys254. Moreover, multiple ZDHHCs are beneficial for palmitoylation of ERK1/2. In contrast, APT2 depalmitoylates ERK1/2. The interaction of RAB27B with ZDHHC9 contributes to MRAS palmitoylation to activate ERK signaling. However, hPAR2 palmitoylation at Cys361 represses ERK signaling. CD36 palmitoylation in hepatocytes facilitates JNK signaling activation. In adipocytes, CD36 palmitoylation is promoted by ZDHHC5 and ZDHHC7 but inhibited by APT1, which facilitates the activation of ERK signaling. PA: palmitic acid.

Figure 7

Regulation of the NLRP3 inflammasome signaling pathways of PRRs mediated by protein palmitoylation After stimulation, NLRP3 recruits ASC and forms an ASC prion-like oligomer to interact with pro-caspase-1 to be composed of an inflammasome, leading to caspase-1 activation. Caspase-1 cleaves gasdermin D (GSDMD) and the proinflammatory cytokines pro-IL1β and pro-IL18, causing the production of the N-terminal fragment GSDMD (GSDMD-NT), IL1β and IL18. Then, GSDMD-NT oligomerizes and forms GSDMD pores in the membrane, leading to the release of IL1β and IL18 and the induction of cell pyroptosis. GSDMD can be palmitoylated at Cys191/Cys192 (human/mouse) to facilitate its cleavage, and its transport to the membrane. ZDHHC5, ZDHHC7, ZDHHC9, and ZDHHC14 have been shown to act as palmitoylases of GSDMD-NT. APT2 inhibits palmitoylation of GSDMD-NT on the membrane, promoting GSDMD oligomerization and the formation of GSDMD pores. In addition, SMPDL38 palmitoylation controlled by ZDHHC5 inhibits NLRP3 inflammasome activation.

Figure 8

The modulation of JAK-STAT signaling by palmitoylation In the JAK-STAT signaling pathway, JAK1, JAK2, STAT1, STAT3, and STAT5α can be palmitoylated. ZDHCC3 and ZDHHC7 can palmitoylate JAK1 at Cys541/542 to facilitate its activation. IFNAR1 palmitoylation at Cys463 benefits STAT1 and STAT2 activation. PA mediated by CD36 control STAT3 palmitoylation. ZDHHC3 and ZDHHC7 promote STAT3 palmitoylation at Cys108. ZDHHC5 increases STAT3 palmitoylation at Cys687 and Cys712. Gp130 palmitoylation mediated by ZDHHC5 and ZDHHC8, and GSK3β palmitoylation at Cys14 mediated by ZDHHC4 contribute to STAT3 activation. In addition, GFAP can be palmitoylated by ZDHHC5, ZDHHC12, ZDHHC21, and ZDHHC23. GFAP palmitoylation at Cys291 mediated by ZDHHC23 facilitates CXCL-10, IL-6, and GM-CSF secretion to activate STAT3. APT2 depalmitoylates STAT3. PA: palmitic acid.