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Functional Characterization of Suppressor of IKKepsilon

Award Number: R21AI107447
ORGANIZATION: NATIONAL INSTITUTE OF ALLERGY & INFECTIOUS DISEASES
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)
PERIOD OF PERFORMANCE START DATE: 02/06/2014
PERIOD OF PERFORMANCE END DATE: 01/31/2017

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Functional Characterization of Suppressor of IKKepsilon - DESCRIPTION (provided by applicant): Pathogen challenge elicits an immediate response by the innate immune system. Multiple innate immune signaling pathways converge to activate TANK binding kinase 1 (TBK1), a ubiquitously expressed kinase. Substrates of TBK1 have proven to be critical players in coordinating host defenses, dictating the shape of the downstream innate immune response. We have defined a new TBK1 substrate, Suppressor of IKK¿ (SIKE). SIKE was first identified as a TBK1 inhibitor. In our studies to define SIKE-mediated TBK1 inhibition, we discovered that SIKE was phosphorylated by TBK1 and the TBK1:SIKE interaction was modulated by SIKE phosphorylation. With respect to other TBK1 substrates, SIKE acted as a nanomolar, mixed-type inhibitor of TBK1. Although SIKE influenced TBK1 activity as a high affinity substrate, SIKE's primary function remains unknown. To address this gap in knowledge, we examined SIKE's localization pattern and interaction network. Gross localization studies indicated that GFP-SIKE was cytosolic, accumulated in cytoskeletal structures, and dense cytosolic granules. Tandem MS/MS data from immunoprecipitated SIKE complexes revealed that SIKE interacted with the cytoskeleton, translation machinery, and mRNA transport proteins associated with ribonucleoprotein complexes (RNPs). RNPs are formed following viral infection to reduce the availability of translation machinery for viral replication. This relationship suggests that RNPs form part of the host's antiviral defenses, yet the linkage between innate immune signaling and these RNA-mediated defenses is poorly defined. Based upon our preliminary data, we hypothesize that SIKE functions as a bridge between the innate immune response and post-transcriptional mRNA pools in cytosolic RNPs to mediate a rapid host response at the level of translation. In Aim 1, we will establish SIKE interactions in epithelial cells that form a defensive barrier to invading pathogen and where rapid RNP formation may represent a key defense mechanism, and phagocytic immune cells responsible for sequestering/removing pathogen where rapid cytoskeletal rearrangement and cell migration are essential functions. We will assess pathogen-specific SIKE interactions using dsRNA in the form of polyinosinic-polycytidylic acid, which mimics key aspects of viral infection, an inducer of RNPs, and S. typhimurium, which is taken up by phagocytic cells and activates TBK1-dependent pathways. In Aim 2, we will examine the impact of SIKE's phosphorylation state on its localization with respect to cell-type and pathogen stimuli. We will investigate SIKE' function at the cell periphery in association with the cytoskeleton versus its role in cytosolic granules through functional assays including cell migration, phagocytosis, formation of pathogen containing vacuoles, and RNP formation and resolution. These studies to determine SIKE's function in bridging TBK1-mediated innate immune responses and RNA granules will provide critical new insight into how TBK1 shapes our innate immune defenses and establish a foundation for building long-term studies on the function, regulation and viral subversion of TBK1-mediated innate immune responses.


Issue Date FY	Funding FY	Legal Entity Name	Legal Entity Address	Legal Entity City	Legal Entity State	Legal Entity Zip Code	Legal Entity COUNTY	Legal Entity COUNTRY	Assistance Listing	Award Code	Budget Year	Action Date	Action Type	Action Amount

Issue Date FY: 2017 ( Subtotal = $0 )
2017	2015	UNIVERSITY OF SAN DIEGO	5998 ALCALA PARK FRNT	SAN DIEGO	CA	92110	SAN DIEGO	USA	Allergy and Infectious Diseases Research	000	2	6/5/2017	CHANGE OF GRANTEE / TRAINING INSTITUTION / AWARDING INSTITUTION	$0
														Subtotal = $0

Issue Date FY: 2015 ( Subtotal = $154,015 )
2015	2015	UNIVERSITY OF SAN DIEGO	ALCALA PARK	SAN DIEGO	CA	92110	SAN DIEGO	USA	Allergy and Infectious Diseases Research	000	2	1/31/2015	CHANGE OF GRANTEE / TRAINING INSTITUTION / AWARDING INSTITUTION	$154,015
														Subtotal = $154,015

Issue Date FY: 2014 ( Subtotal = $216,312 )
2014	2014	VIRGINIA COMMONWEALTH UNIVERSITY	327 WEST MAIN STREET	RICHMOND	VA	23284	RICHMOND CITY	USA	Allergy and Infectious Diseases Research	002	1	9/16/2014	NEW	$0
2014	2014	VIRGINIA COMMONWEALTH UNIVERSITY	327 WEST MAIN STREET	RICHMOND	VA	23284	RICHMOND CITY	USA	Allergy and Infectious Diseases Research	001	1	6/26/2014	NEW	$21,631
2014	2014	VIRGINIA COMMONWEALTH UNIVERSITY	327 WEST MAIN STREET	RICHMOND	VA	23284	RICHMOND CITY	USA	Allergy and Infectious Diseases Research	000	1	2/6/2014	NEW	$194,681
														Subtotal = $216,312

Grand Total All Awards = $370,327

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Functional Characterization of Suppressor of IKKepsilon

Award Number: R21AI107447

ORGANIZATION: NATIONAL INSTITUTE OF ALLERGY & INFECTIOUS DISEASES

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)

PERIOD OF PERFORMANCE START DATE: 02/06/2014

PERIOD OF PERFORMANCE END DATE: 01/31/2017

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