The interaction of p62 with RIP links the atypical PKCs to NF-kappa B activation

Abstract

The two members of the atypical protein kinase C (aPKC) subfamily of isozymes (ζPKC and λ/ιPKC) are involved in the control of nuclear factor κB (NF-κB) through IKKβ activation. Here we show that the previously described aPKC-binding protein, p62, selectively interacts with RIP but not with TRAF2 in vitro and in vivo. p62 bridges the aPKCs to RIP, whereas the aPKCs link IKKβ to p62. In this way, a signaling cascade of interactions is established from the TNF-R1 involving TRADD/RIP/p62/aPKCs/IKKβ. These observations define a novel pathway for the activation of NF-κB involving the aPKCs and p62. Consistent with this model, the expression of a dominant-negative mutant λ/ιPKC impairs RIP-stimulated NF-κB activation. In addition, the expression of either an N-terminal aPKC-binding domain of p62, or its C-terminal RIP-binding region are sufficient to block NF-κB activation. Furthermore, transfection of an antisense construct of p62 severely abrogates NF-κB activation. Together, these results demonstrate that the interaction of p62 with RIP serves to link the atypical PKCs to the activation of NF-κB by the TNFα signaling pathway.

p62/SQSTM1 at the interface of aging, autophagy, and disease

“…Thus, loss of p62/SQSTM1 with age may contribute to the increased fat accumulation and metabolic dysfunctions seen in the elderly. Consistent with this hypothesis, p62/SQSTM1 is necessary for PKCζ activity (Sanz et al 1999), which counteracts glucose intolerance by reducing the production of pro-inflammatory cytokines in mouse's white adipocytes (Lee et al 2010). p62/SQSTM1 expression may also favor the differentiation of brown over white adipocytes: knockout of Atg7 in white adipose tissue causes the white adipocytes to acquire features of brown adipocytes, including increased mitochondrial mass, increased β-oxidation and mitochondrial uncoupling, and formation of multiple lipid droplets per cell, instead of a single big lipid vacuole (Zhang et al 2009).…”

“…Although p62/SQSTM1 may mediate transcription in the nucleus through the ZZ domain, this domain is primarily involved in cytoplasmic signaling cascades and is in fact necessary to bind the receptor-interacting protein 1 (RIP1) kinase in the TNF receptor (TNF-R) complex. Binding of p62/SQSTM1 to RIP1 allows signaling of the TNF-R through protein kinase C (PKC) and activation of nuclear factor-kappaB (NFkB) (Sanz et al 1999).…”

“…Signal transduction p62/SQSTM1 is involved in several signal transduction cascades (Sanz et al 1999;Jin et al 2009). p62/ SQSTM1 serves as a scaffold to bring together two or more components of a signaling pathway, but it is not phosphorylated or otherwise modified by these signaling cascades, nor it has any catalytic activity of its own.…”

“…p62/ SQSTM1 serves as a scaffold to bring together two or more components of a signaling pathway, but it is not phosphorylated or otherwise modified by these signaling cascades, nor it has any catalytic activity of its own. For example, in TNF-R signaling, the ZZ domain of p62/SQSTM1 binds the active RIP1 kinase and the PB1 domain binds protein kinase C λ/ι (PKC λ/ι), bringing them together into a signaling complex (Sanz et al 1999). This complex forms upon stimulation of the TNF-R and is necessary to activate NFkB, since disrupting the ZZ domain or reducing the expression of p62/SQSTM1 impairs TNFα-mediated NFkB activation (Sanz et al 1999).…”

“…For example, in TNF-R signaling, the ZZ domain of p62/SQSTM1 binds the active RIP1 kinase and the PB1 domain binds protein kinase C λ/ι (PKC λ/ι), bringing them together into a signaling complex (Sanz et al 1999). This complex forms upon stimulation of the TNF-R and is necessary to activate NFkB, since disrupting the ZZ domain or reducing the expression of p62/SQSTM1 impairs TNFα-mediated NFkB activation (Sanz et al 1999). In addition to TNF-R, the interleukin-1β receptor (IL-1βR) and the nerve growth factor receptors TrkA and p75 NTR recruit p62/SQSTM1 to facilitate signaling to NFkB (Sanz et al 2000;Wooten et al 2001).…”