Phosphorylated Hsp27 prevents LPS‐induced excessive inflammation in THP‐1 cells via suppressing ROS‐mediated upregulation of CBP

Abstract

Heat shock protein 27 (Hsp27) is a member of the small heat shock protein family expressed at high levels to protect cells against heat shock and other conditions of stress. Hsp27 has been indicated in the regulation of inflammation signaling pathway, and Hsp27 phosphorylation is vital for efficient control of host‐defense response in early stages of lipopolysaccharide (LPS)‐stimulated inflammation. The notion that CREB‐binding protein (CBP) is involved in the regulation of two major transcription factors, nuclear factor‐κB (NF‐κB) and AP‐1, suggests that CBP, as a coactivator protein, may also play an important role in the cellular response to inflammation. Here, we explored the mechanism underlying the regulatory relationships between Hsp27 and CBP in THP‐1 cells, and found that phosphorylated Hsp27 was critical to the protein level of CBP. Furthermore, in exploring the signaling mechanisms underlying its action, we found that p38MAPK‐MK2‐Hsp27 regulated NF‐κB via CBP, which acted as a multi‐protein complex assembly scaffold. Finally, we demonstrated that phosphorylated Hsp27 reduced reactive oxygen species accumulation thereby significantly repressed LPS‐induced excessive increase of CBP. Taken together, our data demonstrated that Hsp27, in its phosphorylation state, plays a critical role in controlling LPS‐induced inflammatory response by modulating CBP.

Spinal heat shock protein 27 participates in PDGFRβ‐mediated morphine tolerance through PI3K/Akt and p38 MAPK signalling pathways

“…Oligomerized unphosphorylated HSP27 may assist with protein folding (Jakob, Gaestel, Engel, & Buchner, 1993; Rogalla et al, 1999). Phosphorylated HSP27 accompanied by a decrease in oligomer size (Jovcevski et al, 2015) either protects cells against heat shock response and LPS‐induced hyperinflammation (Bi, Jiang, Zhou, Luo, & Yin, 2019; Lavoie et al, 1995) or arrests unphosphorylated HSP27 chaperone activity (Arrigo, 2001). Here, unphosphorylated and phosphorylated HSP27 were up‐regulated by chronic morphine administration and simultaneously inhibited by HSP27‐RNAi‐LV but not NC‐LV transfection which, in turn, attenuated morphine tolerance.…”

Microglial Polarization: Novel Therapeutic Strategy against Ischemic Stroke

“…CREB-binding protein (CBP) is another competition site. The increase of CREB activity has a negative effect on the combination of CBP and NF-κB [ 65 , 66 ]. With the activation of TLRs, interferon regulatory factor-3 (IRF-3) is phosphorylated and interacts with CBP promoting the M2 polarization.…”

Reductive Stress-Induced Mitochondrial Dysfunction and Cardiomyopathy

“…Activation of MAPK by ROS is also proven to protect cells against death [93]. Although pHsp27 decreases ROS accumulation and could constrain cardiac cell death [94][95][96], overexpression of Hsp27 can lead to reductive stress and contributes to cardiomyopathy ( Figure 5) [97,98]. However, other studies showed that overexpression of Hsp27 could protect myocardium during ischemic stress [95,[99][100][101].…”

“…CryAB, an ER chaperone [106], is substantially expressed in the heart, where it constitutes as much as 5% of total heart protein [107]. CryAB, with its wide-spectrum chaperone activities [108], promotes the folding of multipath transmembrane proteins from the cytosolic face of the [94][95][96]. However, overexpression of Hsp27 leading to cardiomyopathy or protecting myocardium is controversial [95,[97][98][99][100][101].…”