Abstract
Nuclear envelope (NE) and endoplasmic reticulum (ER) collaborate to control a multitude of nuclear and cytoplasmic actions. In this context, the transmembrane protein TMEM147 localizes to both NE and ER, and through direct and indirect interactions regulates processes as varied as production and transport of multipass membrane proteins, neuronal signaling, nuclear-shape, lamina and chromatin dynamics and cholesterol synthesis. Aiming to delineate the emerging multifunctionality of TMEM147 more comprehensively, we set as objectives, first, to assess potentially more fundamental effects of TMEM147 on the ER and, second, to identify significantly TMEM147-associated cell-wide protein networks and pathways. Quantifying curved and flat ER markers RTN4 and CLIMP63/CKAP4, respectively, we found that TMEM147 silencing causes area and intensity increases for both RTN4 and CLIMP63, and the ER in general, with a profound shift toward flat areas, concurrent with reduction in DNA condensation. Protein network and pathway analyses based on comprehensive compilation of TMEM147 interactors, targets and co-factors then served to manifest novel and established roles for TMEM147. Thus, algorithmically simplified significant pathways reflect TMEM147 function in ribosome binding, oxidoreductase activity, G protein-coupled receptor activity and transmembrane transport, while analysis of protein factors and networks identifies hub proteins and corresponding pathways as potential targets of TMEM147 action and of future functional studies.
Highlights
Transmembrane Protein 147 (TMEM147), known as NIFIE14, is a small, fairly recently discovered protein that localizes to the endoplasmic reticulum (ER) [1,2]
There, early embryonic development is controlled by the NODAL signal transduction pathway, which Haffner and co-workers found to be modulated by a protein complex containing Nicalin and NOMO [7]
In analogy to our previous analyses of TMEM147 and Lamin B receptor (LBR) concerning the Nuclear envelope (NE), we investigated the effect of TMEM147 silencing on CLIMP63 and Rtn as markers and potential facilitators of TMEM147 ER action
Summary
Transmembrane Protein 147 (TMEM147), known as NIFIE14, is a small, fairly recently discovered protein that localizes to the endoplasmic reticulum (ER) [1,2]. The most abundant of the latter three in-frame variants is the largest and translates to a 224amino-acid (aa) protein of 26.2 kDa (see Table 1 and Supplementary Figures S1–S3). TMEM147 has seven transmembrane domains, each of which fully span the ER membrane, with the N-terminus facing the ER lumen and the C-terminus facing the cytosol [5]. Its expression in many tissues [6] (see Supplementary Figure S4) suggests its general and wide-ranging physiological role, as does the high level of conservation of the TMEM147 gene across mammals, with sequence similarity in human, mouse, rat and bovine species of up to 99% [1,2]. There, early embryonic development is controlled by the NODAL signal transduction pathway, which Haffner and co-workers found to be modulated by a protein complex containing Nicalin and NOMO [7]
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