Disease relevance of PSMD14

• According to the increasing severity of the disease, patients were divided into PAD1 (only diffuse calcifications of the arteries without any stenosis or occlusion), PAD2 (one or two stenosis or occlusions) and PAD3 (three or more) [1].

High impact information on PSMD14

• These effects were reduced by mutation of a cysteine residue in the Mpr1 pad1 N-terminal plus motif of POH1 (Cys-120) and appeared to be selective for c-Jun, because POH1 had no effect on other proteasomal substrates [2].
• Ectopic expression of POH1 in HEK293 cells decreased the level of c-Jun ubiquitination, leading to significant accumulation of the protein and a corresponding increase in AP1-mediated gene expression [2].
• In fission yeast, overexpression of the essential pad1(+) gene confers pleiotropic drug resistance through a pathway involving an AP-1 transcription factor encoded by pap1(+) [3].
• POH1 also confers P-glycoprotein-independent resistance to taxol (paclitaxel), doxorubicin, 7-hydroxystaurosporine, and ultraviolet light when transiently overexpressed in mammalian cells [3].
• Our data demonstrate that PAD3 is the enzyme that deiminates trichohyalin in the medulla and the Henle layer, indicate that PAD1 and 3 are involved in the hair follicle program of differentiation, and suggest a role for PAD1 and 2 in the physiology of sweat glands and arrector pili muscles [4].

Biological context of PSMD14

• Taken together, these results suggest that SmPOH, and possibly other related Pad1 proteins, function as positive modulators of transcription by increasing the stability of cellular c-Jun, making elevated amounts of this protein available for transactivation of AP-1-responsive genes [5].
• Both HCC1 and PAD-1 show amino acid sequence similarities to the human splicing factor, U2AF65 [6].
• To more specifically test for any requirement of the zinc metalloproteinase motif of Poh1 to support cell viability and proteasome function, we developed a RNAi complementation strategy [7].

Anatomical context of PSMD14

• Here, confocal microscopy analysis using highly specific antibodies demonstrated that PAD1 and 3 are expressed in human anagen hair follicles, PAD1 and 2, in arrector pili muscles and sweat glands, whereas no PAD were detected in sebaceous glands [4].
• Moreover, PAD1 and 3 were observed to co-localize with (pro)filaggrin, and PAD2 to be located at the keratinocyte periphery in the stratum granulosum [8].
• Poh1 RNA interference (RNAi) in HeLa cells resulted in a reduction in cell viability and an increase in polyubiquitinated protein levels, supporting the link between Poh1 and the ubiquitin proteasome pathway [7].

Other interactions of PSMD14

• PAD-1 showed 30% identity and 57% similarity to a protein, HCC1, which was isolated using autoantibodies from patients suffering from hepatocellular carcinoma [6].

Analytical, diagnostic and therapeutic context of PSMD14

• Immunoelectron microscopy demonstrated that PAD1 and PAD3 are co-located with filaggrin within the filamentous matrix of the deeper corneocytes where the protein is deiminated [9].

References