Proteostasis in dendritic cells is controlled by the PERK signaling axis independently of ATF4

Abstract

In stressed cells, phosphorylation of eukaryotic initiation factor 2α (eIF2α) controls transcriptome-wide changes in mRNA translation and gene expression known as the integrated stress response. We show here that DCs are characterized by high eIF2α phosphorylation, mostly caused by the activation of the ER kinase PERK (EIF2AK3). Despite high p-eIF2α levels, DCs display active protein synthesis and no signs of a chronic integrated stress response. This biochemical specificity prevents translation arrest and expression of the transcription factor ATF4 during ER-stress induction by the subtilase cytotoxin (SubAB). PERK inactivation, increases globally protein synthesis levels and regulates IFN-β expression, while impairing LPS-stimulated DC migration. Although the loss of PERK activity does not impact DC development, the cross talk existing between actin cytoskeleton dynamics; PERK and eIF2α phosphorylation is likely important to adapt DC homeostasis to the variations imposed by the immune contexts.

Antigen-derived peptides directly engage the unfolded-protein sensor IRE1α to curb cross-presentation by dendritic cells

“…Our BMDC studies showed that antigen pulsing selectively activates IRE1α but not PERK or ATF6, excluding the standard UPR as a key mechanistic driver. This contrasts with plasmacytoid DCs (pDCs), which do not mediate cross-presentation, and interestingly display constitutive activation of PERK (Mendes et al, 2021). BMDC pulsing with different protein antigens, or with lysates of several cancer cell lines, induced significant levels of IRE1α activity.…”

The Unfolded Protein Response in Immune Cells as an Emerging Regulator of Neuroinflammation

“…IRE1 via XBP1s controls eosinophil, DC, and plasma cell development (Reimold et al, 2001;Iwakoshi et al, 2007;, which contribute to neuroinflammation in MS and Experimental Autoimmune Encephalomyelitis (EAE), the mouse model of MS (Greter et al, 2005;Wensky et al, 2005;Mundt et al, 2019;Pröbstel et al, 2020). Furthermore, DCs and plasma cells show constitutive UPR activation and display an elevated protein synthesis rate in steady state (Osorio et al, 2014;Khalsa et al, 2019;Mendes et al, 2020). In these cell types, XBP1s maintains ER architecture, whereas RIDD controls functional aspects, including antigen cross-presentation and cDC1s survival, or immunoglobulin production by plasma cells (Benhamron et al, 2014;Osorio et al, 2014;Tavernier et al, 2017).…”

“…In these cell types, XBP1s maintains ER architecture, whereas RIDD controls functional aspects, including antigen cross-presentation and cDC1s survival, or immunoglobulin production by plasma cells (Benhamron et al, 2014;Osorio et al, 2014;Tavernier et al, 2017). PERK signaling is also active in DCs (Mendes et al, 2020), whereas ATF6 remains understudied in immunity. These findings suggest that IRE1 and PERK signaling could be targets in neuroinflammatory pathologies involving DCs and plasma cell function, such as EAE (Greter et al, 2005;Mundt et al, 2019;Pröbstel et al, 2020).…”

“…PERK also controls IL-23 synthesis via CHOP (Goodall et al, 2010), and it promotes IL-6, CCL2, and CCL20 production in astrocytes via JAK1-STAT3 (Meares et al, 2014;Sanchez et al, 2019). PERK also promotes IFN-I production in DCs (Mendes et al, 2020), and it controls macrophage/myeloid cell function in atherosclerosis and cancer models (DeVries-Seimon et al, 2005;Erbay et al, 2009;Thevenot et al, 2014;Mohamed et al, 2020).…”

Endoplasmic Reticulum Quality Control in Immune Cells

“…Different from acute ER stress, the phosphorylation levels of eIF2α in the spleen and FLT3L BMDCs were significantly increased under steady-state conditions ( Mendes et al, 2021 ). During the DC differentiation process, PERK was activated, which contributed to a high level of p-eIF2α.…”