DISSECTING THE ROLES OF WHIP-TRIM14-PPP6C IN INNATE ANTIVIRAL IMMUNITY AND MYELOID BECLIN1 IN TUMOR IMMUNITY
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Date
2018-05-07
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Abstract
The innate immune system has the ability to tune the inflammatory environment by
modulating pathogen-recognition receptors (PRRs) signaling, which can either induce oncogenic
changes or generate antitumor immunity through cross-talking with adaptive immunity. Thus, tight
regulation of innate immune signaling pathways is essential either for an effective immune
response against viral infections and tumor or for preventing detrimental autoimmunity.
Mitochondrial antiviral-signaling protein MAVS acts as a central hub for RIG-I receptor
proximal signal propagation. However, key components in the assembly of the MAVS
mitochondrial platform that promote RIG-I mitochondrial localization and optimal activation are
still largely undefined. Employing pooled RNAi and yeast two-hybrid screenings, we report that
the mitochondrial adaptor protein TRIM14 provides a docking platform for the assembly of the
mitochondrial signaling complex required for maximal activation of RIG-I-mediated signaling,
consisting of WHIP and protein phosphatase PPP6C. Following viral infection, the ubiquitin-binding
domain in WHIP bridges RIG-I with MAVS through the binding to polyUb chains of RIGI
at lysine 164. ATPase domain in WHIP contributes to the stabilization of RIG-I-dsRNA
interaction. Moreover, phosphatase PPP6C is responsible for RIG-I dephosphorylation. Together,
our findings define the WHIP-TRIM14-PPP6C mitochondrial signalosome required for RIG-I-mediated
innate antiviral immunity.
Giving the embryonic lethality of Beclin1 (Becn1) homozygous mice, roles of myeloid
Becn1 in cancer-associated inflammation and tumor immunity remain elusive. We demonstrate
herein that mice with myeloid loss of Becn1 (Becn1^ΔM) show high risk of precursor (pre)-B cell
lymphoma associated with neutrophilia. Becn1 deficiency stabilizes neutrophil MEKK3
independent of autophagy, resulting in the aberrant p38 activation and exaggerated tumorigenic
inflammation that triggers the expressions of PD-L1 and pro-survival genes in pre-B cells.
Importantly, we identify low Becn1 expression of neutrophils correlates with programmed death
ligand 1 (PD-L1) levels and cancer recurrence in patients with pre-B acute lymphoblastic
lymphoma (ALL). In a mouse model of melanoma, expansion and infiltration of neutrophils and
B cells due to Becn1 deficiency favor metastasis of B16 melanoma. Thus, homeostatic
maintenance of Becn1 level in neutrophils will contribute to the outcome of the tumorigenic
process of pre-B cells.
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Keywords
Innate Immunity, Tumor Immunity