Abstract
GJB2 mutations are the leading cause of non-syndromic inherited hearing loss. GJB2 encodes connexin-26 (CX26), which is a connexin (CX) family protein expressed in cochlea, skin, liver, and brain, displaying short cytoplasmic N-termini and C-termini. We searched for CX26 C-terminus binding partners by affinity capture and identified 12 unique proteins associated with cell junctions or cytoskeleton (CGN, DAAM1, FLNB, GAPDH, HOMER2, MAP7, MAPRE2 (EB2), JUP, PTK2B, RAI14, TJP1, and VCL) by using mass spectrometry. We show that, similar to other CX family members, CX26 co-fractionates with TJP1, VCL, and EB2 (EB1 paralogue) as well as the membrane-associated protein ASS1. The adaptor protein CGN (cingulin) co-immuno-precipitates with CX26, ASS1, and TJP1. In addition, CGN co-immunoprecipitation with CX30, CX31, and CX43 indicates that CX association is independent on the CX C-terminus length or sequence. CX26, CGN, FLNB, and DAMM1 were shown to distribute to the organ of Corti and hepatocyte plasma membrane. In the mouse liver, CX26 and TJP1 co-localized at the plasma membrane. In conclusion, CX26 associates with components of other membrane junctions that integrate with the cytoskeleton.
Highlights
The GJB2 gene encodes connexin 26 (CX26), which is a protein that plays central roles in hearing, promoting cochlear development, and sustaining auditory function in the mature cochlea [1,2,3,4]
Some heterozygous GJB2 mutations behave in a dominant fashion, which leads to non-syndromic autosomal dominant hearing loss or to the keratitis-ichthyosis-deafness syndrome [10]
Connexins (CX) assemble intercellular gap junctions (GJ), which result from the interaction between two distinct hemi-channels from adjacent cells with each composed of six CX units
Summary
The GJB2 gene encodes connexin 26 (CX26), which is a protein that plays central roles in hearing, promoting cochlear development, and sustaining auditory function in the mature cochlea [1,2,3,4]. GJB2 mutations are the most frequent cause of non-syndromic recessive hearing loss across diverse populations [6,7,8,9]. Some heterozygous GJB2 mutations behave in a dominant fashion, which leads to non-syndromic autosomal dominant hearing loss or to the keratitis-ichthyosis-deafness syndrome [10]. Among mouse CX family members, CX26 has the second lowest molecular mass due to shorter segments outside the four transmembrane domains (the extracellular and intracellular loops as well as N-termini and C-termini). Due to its limited length, few binding partners have been identified for CX26 cytosolic segments, e.g., amino-termini and carboxyl-termini and the loop between the second and third transmembrane domains [19,20,21]
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