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TNFR1-activated NF-kB signal transduction: regulation
by the ubiquitin/proteasome system
Ingrid E Wertz
The Tumor Necrosis Factor Receptor-1 (TNFR1) is a central
regulator of inflammation, cell death, and cellular proliferation.
As such, alterations in TNFR1 signaling are associated with
numerous diseases ranging from autoimmune syndromes to
cancer. Understanding the regulation of TNFR1 signaling is
therefore of considerable importance. The transduction of
signaling events in the TNFR1 pathway from ligand binding
through transcriptional regulation is regulated at nearly every
step by post-translational modifications, including
ubiquitination. In this review both endogenous and
pharmacologic inhibitors of TNFR1 signaling, and how these
impact the ubiquitin system, will be discussed.
Addresses
Departments of Molecular Oncology and Early Discovery Biochemistry,
Genentech, Inc., 1 DNA Way, M/S 40, South San Francisco, CA 94080,
United States
Corresponding author: Wertz, Ingrid E (wertz.ingrid@gene.com)
Introduction
Tumor Necrosis Factor (TNF) was first described in
1975 as an endotoxin-induced factor that caused tumor
necrosis in a sarcoma mouse model [1]. It is now known that
TNF activates inflammatory responses, induces apoptosis
and necroptosis, regulates cellular proliferation, and may
even promote cancer progression. The effects of TNF are
transduced by TNF Receptor-1 (TNFR1) and TNFR2.
Studies with TNFR1-deficient and TNFR2-deficient
mice indicate that TNFR1 mediates most of the proliferation, pro-inflammatory, and cell death-activating pathways. TNFR2 signaling also impacts tissue repair and
angiogenesis and, as TNFR2 signaling is less well characterized [2,3]; this review will thus focus on TNFR1induced signaling. TNFR1 signal transduction is complex
and promotes diverse outcomes, many of which are
mediated by the transcription factor NFkB that will be
the subject of this review. Given the variable and essential
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consequences of TNFR1-mediated signaling, it is important to understand the regulation of this pathway. The
ubiquitin/proteasome system has recently emerged as a
critical regulatory mechanism of intracellular signal transduction. Avid research in the past 1520 years has identified a number of proteins in the TNFR1 transduction
cascade that are modified by ubiquitination. This review
will highlight both endogenous and pharmaceutical inhibitors of TNFR1-activated NFkB signaling, many of which
impact the ubiquitin/proteasome system.
72 Molecular immunology
Figure 1
TNF
antagonists
TNF
TNFR1
Ub Ub
Ub
Ub Ub Ub
Ub
cIAP1/2
Ub
TAB1 CYLD Ub
Ub
TAB2/3
TAK1
NEMO
Ub
Ub
Ub
IAP
antagonists
Ub
IKK IKK
P
LUBAC
proteasome
inhibitors
MKK3
MKK4
Ub Ub Ub
Ub
IB P
p50 p65
JNK
p38
proteasome
IB
NFB
c-jun
ATF2
Ubiquitin chain key
Ub
K48-linked
Ub
K63-linked
Ub
linear
transcription
cell survival
proliferation
inflammation
TNFR1 signal transduction to NFkB activation. The liganded receptor is shown with the proximal signaling complex assembled. Ubiquitin
modifications are also shown, as are phosphorylation events. Ubiquitin-mediated assembly of signaling complexes via K63-linked and linear
chains promotes sequential kinase activation that ultimately results in transcription factor activation. Endogenous inhibitors are indicated in red
whereas pharmaceutical inhibitors are indicated in blue. Not shown: the LUBAC ubiquitin ligase complex promotes linear polyubiquitination of
TNFR1 signaling components including NEMO and RIPK1.
Table 1
A summary of endogenous inhibitors of TNFR1-activated NFkB signaling
Cellular targets
Endogenous
inhibitor
Mechanisms of action
Knockout phenotypea
of protein inhibitor
CYLD
Enhanced inflammation
and tumor formation
A20
OTULIN
HOIP, Disheveled-2
Enhanced inflammation
Hypermorphic mutants have
due to constitutive NFkB impaired responses to infectious
activity
diseases
Table 2
A summary of pharmaceutical inhibitors of TNFR1-activated NFkB signaling
Chemical inhibitor
Knockout phenotypea
of inhibitor target
Cellular targets
Mechanisms of action
TNF antagonists
Depressed recovery
from infectious challenges,
decreased granuloma
formation, enhanced LPS
toxicity of D-gal-treated mice
Autoimmune syndromes
including rheumatoid arthritis,
inflammatory bowel disease,
psoriasis
IAP antagonists
IAP proteins
Promote cIAP
autoubiquitination and
degradation
Block XIAP caspase
binding to enhance
cell death
Numerous malignancies,
chemotherapy resistance,
X-linked lymphoproliferative
syndrome type-2
Proteasome
inhibitors
Primarily PSMB5
(chymotrypsin-like
activity)
Reversible and
irreversible enzyme
inhibition
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74 Molecular immunology
OTULIN is an OTU domain-containing DUB that attenuates TNF-activated NFkB signaling, similar to A20 and
CYLD, yet is unique in its selectivity for linear ubiquitin
chains [45,46]. OTULIN functionally reverses
LUBAC-mediated linear ubiquitination of TNFR1 signaling complex proteins to attenuate NFkB activity [46]
and has also been implicated in angiogenesis, WNT signaling and in Toll-like receptor and NOD2-mediated
immunity [45,47]. OTULIN is recruited to TNFR1
via HOIP within the LUBAC complex, and phosphorylation of OTULIN or mutation of critical HOIP-interacting
residues blocks association with HOIP, thereby resulting
in enhanced TNF-activated NFkB activity [48,49].
IkB proteins
TNF antagonists
yeast Pre2, the PSMB5 ortholog [59]. Given the ubiquitous function of the proteasome, it is no surprise that
proteasome inhibitors are reported to promote cell death
via a multitude of molecular mechanisms. These include
stabilization of pro-apoptotic Bcl-2 family members, inhibition of canonical and noncanonical NFkB pathways,
disruption of interactions between tumor and stromal
cells, accumulation of misfolded proteins and proteasome
substrates such as b-catenin, and induction of cell cycle
arrest due to accumulation of cyclin B1 and p21 cell
cycle regulators [6062]. More specifically, Bortezomib
inhibits NFkB pro-survival function by blocking TNFinduced IkBa degradation and thereby promotes cell
death [63]. On the other hand, in chronic lymphocytic
leukemia cells, Carfilzomib has been shown to promote
atypical NFkB activation as indicated by phosphorylation
and loss of IkBa and increased DNA binding of the
NFkB heterodimer, yet without subsequent increases
in canonical NFkB target gene transcription [64].
Future directions
Here we have reviewed some of the endogenous proteins
and pharmaceutical compounds that regulate TNFR1activated NFkB signaling, with a focus on ubiquitinmediated regulation. While the complexity of this signaling pathway poses challenges to the facile and complete understanding of the molecular regulatory
mechanisms, it also presents numerous opportunities
for pharmacological intervention. The pharmaceutical
industry is avidly exploring such opportunities and, given
the clinical success in these endeavors combined with the
multi-faceted roles of the targeted proteins in various
pathological conditions, it makes sense to not only
identify novel targets for pharmacological intervention
but also to repurpose the utility of selective compounds in
alternate disease indications [65].
Acknowledgement
Thank you to Allison Bruce for graphical assistance.
Proteasome inhibitors
Bortezomib (Velcade) was the first FDA-approved proteasome inhibitor and has shown efficacy for the treatment of multiple myeloma and mantle cell lymphoma
[58]. Bortezomib is a slowly reversible peptide boronate
inhibitor that primarily targets proteasomal chymotrypsin-like activity, that is afforded by the PSMB5 subunit.
Carfilzomib (Kyprolis) is a second-generation epoxyketone proteasome inhibitor that is a highly selective,
irreversible inhibitor of chymotrypsin-like activity. The
importance of proteasomal chymotrypsin-like activity is
confirmed by the lethal phenotype of knockout strains of
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1.
2.
3.
4.
5.
76 Molecular immunology
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14. Kulathu Y, Akutsu M, Bremm A, Hofmann K, Komander D: Twosided ubiquitin binding explains specificity of the TAB2 NZF
domain. Nat Struct Mol Biol 2009, 16:1328-1330.
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