Elucidation Of Regulation And Function Of WISP3
IR@IICB: CSIR-Indian Institute of Chemical Biology, Kolkata
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| Title |
Elucidation Of Regulation And Function Of WISP3
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| Creator |
Patra, Milan
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| Subject |
Cancer Biology and Inflammatory Disorder Division
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| Description |
WISP3 (Wnt Induced Signaling Protein 3) is a member of the CCN (Cysteine rich 61, Connective tissue growth factor, Nephroblastoma overexpressed protein) family proteins, and
expressed in cells and tissues of mesenchymal origin. As suggested and published by the International CCN Society, the alternative name of WISP3 is CCN6. WISP3 maps to human
chromosome 6q-22 and codes for a 354 amino acid multi-domain protein. Mutations of WISP3 are associated with Progressive Pseudo Rheumatoid Dysplasia (PPRD) which is characterized by degeneration of cartilage, narrowing of joint space and stunted bone growth at the onset of
puberty. Prior investigations suggest that most of these CCN proteins are mainly involved in the regulation of chondrogenesis and angiogenesis. In spite of a number of studies focusing on the functional characterization of WISP3 in context of chondrocyte differentiation and cartilage growth / development, the detailed molecular mechanism of WISP3 function remains incomplete. The goal of this thesis work is to explore the function and regulation of WISP3. Given that WISP3 has its influence on ROS accumulation and mitochondria are the major site of
ROS production, WISP3 may regulate mitochondrial ROS by influencing mitochondrial functions. Besides, the multi-domain architecture of WISP3 suggests that it may interact with mitochondrial protein HSP60 and ATP5A1, and the WISP3 interaction network may regulate mitochondrial functions. Here, for the first time we found that WISP3 localizes to mitochondria and depletion of WISP3 enhances mitochondrial ROS accumulation within physiological limit. Additionally, WISP3 depletion by siRNA enhances mitochondrial ATP synthesis, mitochondrial membrane potential, calcium uptake, ROS dependent PGC1α expression and mitochondrial
mass. We demonstrated that WISP3 associates with mitochondrial proteins including HSP60. Upon depletion of WISP3 expression by siRNA, interaction of HSP60 with mitochondrial Complex I subunit NDUFB8 changes, concomitant with enhanced Complex I activity of mitochondrial electron transport chain (ETC). Enhanced ETC activity is documented by elevated Complex I assembly. A similar outcome of WISP3 depletion using CRISPR-Cas9 validates that WISP3 modulates Complex I assembly and thereby mitochondrial function. Transcription factor Nrf2 counter regulates WISP3 function through repressing WISP3 expression. Taken together,
our results document for the first time that WISP3 plays an inhibitory role appropriately balanced by Nrf2 in mitochondrial ETC complex assembly and activity.
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| Date |
2016-06-09
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| Type |
Thesis
NonPeerReviewed |
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| Format |
application/pdf
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| Identifier |
http://www.eprints.iicb.res.in/2568/1/thesis_Milan_Patra.pdf
Patra, Milan (2016) Elucidation Of Regulation And Function Of WISP3. PhD thesis, C U . |
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| Relation |
http://www.eprints.iicb.res.in/2568/
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