RNF-121 is an endoplasmic reticulum-membrane E3 ubiquitin ligase involved in the regulation of beta-integrin.
We report on the characterization of RNF-121, an evolutionarily conserved E3 ligase RING finger protein that is expressed in the endoplasmic reticulum (ER) of various cells and tissues in Caenorhabditis elegans. Inactivation of RNF-121 induced an elevation in BiP expression and increased the sensitivity of worms to ER stress. Genetic analysis placed RNF-121 downstream of the unfolded protein response (UPR) regulator protein kinase-like endoplasmic reticulum kinase (PERK). We identify PAT-3::GFP, the beta subunit of the heterodimeric integrin receptors, as an RNF-121 substrate; whereas induction of RNF-121 expression reduced the level of PAT-3::GFP in the gonad distal tip cells, inhibition of RNF-121 led to the accumulation of stably bound PAT-3::GFP inclusions. Correspondingly, overexpression of RNF-121 during early stages of gonad development led to aberrations in germline development and gonad migration that overlap with those observed after PAT-3 inactivation. The formation of these gonad abnormalities required functional ER-associated degradation (ERAD) machinery. Our findings identify RNF-121 as an ER-anchored ubiquitin ligase that plays a specific role in the ERAD pathway by linking it to the regulation of the cell adhesion integrin receptors.
Darom
Amir
A
Department of Cell and Developmental Biology, Sackler School of Medicine, Tel Aviv University, Tel Aviv, Israel.
Bening-Abu-Shach
Ulrike
U
Broday
Limor
L
D000818:Animals; D030801:Animals, Genetically Modified; D017173:Caenorhabditis elegans / Q000033:anatomy & histology / Q000378:metabolism; D029742:Caenorhabditis elegans Proteins / Q000235:genetics / Q000378:metabolism*; D018797:Cell Cycle Proteins / Q000235:genetics / Q000378:metabolism; D004721:Endoplasmic Reticulum / Q000201:enzymology*; D006066:Gonads / Q000002:abnormalities / Q000378:metabolism; D006360:Heat-Shock Proteins / Q000235:genetics / Q000378:metabolism; D039641:Integrin beta Chains / Q000235:genetics / Q000378:metabolism*; D048369:MAP Kinase Kinase 1 / Q000235:genetics / Q000378:metabolism; D054829:RING Finger Domains; D034622:RNA Interference; D011993:Recombinant Fusion Proteins / Q000235:genetics / Q000378:metabolism; D015398:Signal Transduction / Q000502:physiology; D013312:Stress, Physiological; D044767:Ubiquitin-Protein Ligases / Q000235:genetics / Q000378:metabolism*; D019892:eIF-2 Kinase / Q000235:genetics / Q000378:metabolism
D029742:Caenorhabditis elegans Proteins; D018797:Cell Cycle Proteins; D006360:Heat-Shock Proteins; D039641:Integrin beta Chains; D048369:MAP Kinase Kinase 1; D011993:Recombinant Fusion Proteins; D044767:Ubiquitin-Protein Ligases; D019892:eIF-2 Kinase; C502196:Hsp-4 protein, C elegans; C093515:pat-3 protein, C elegans; C552941:RNF-121 protein, C elegans; C499574:pek-1 protein, C elegans