Derlin rhomboid pseudoproteases employ substrate engagement and lipid distortion to enable the retrotranslocation of ERAD membrane substrates
Anahita Nejatfard,
Nicholas Wauer,
Satarupa Bhaduri,
Adam Conn,
Saroj Gourkanti,
Narinderbir Singh,
Tiffany Kuo,
Rachel Kandel,
Rommie E. Amaro,
Sonya E. Neal
Affiliations
Anahita Nejatfard
Division of Biological Sciences, Section of Cell and Developmental Biology, University of California San Diego, La Jolla, CA 92093, USA
Nicholas Wauer
Department of Chemistry and Biochemistry, University of California San Diego, La Jolla, CA 92093, USA
Satarupa Bhaduri
Division of Biological Sciences, Section of Cell and Developmental Biology, University of California San Diego, La Jolla, CA 92093, USA
Adam Conn
Division of Biological Sciences, Section of Cell and Developmental Biology, University of California San Diego, La Jolla, CA 92093, USA
Saroj Gourkanti
Division of Biological Sciences, Section of Cell and Developmental Biology, University of California San Diego, La Jolla, CA 92093, USA
Narinderbir Singh
Division of Biological Sciences, Section of Cell and Developmental Biology, University of California San Diego, La Jolla, CA 92093, USA
Tiffany Kuo
Division of Biological Sciences, Section of Cell and Developmental Biology, University of California San Diego, La Jolla, CA 92093, USA
Rachel Kandel
Division of Biological Sciences, Section of Cell and Developmental Biology, University of California San Diego, La Jolla, CA 92093, USA
Rommie E. Amaro
Department of Chemistry and Biochemistry, University of California San Diego, La Jolla, CA 92093, USA
Sonya E. Neal
Division of Biological Sciences, Section of Cell and Developmental Biology, University of California San Diego, La Jolla, CA 92093, USA; Corresponding author
Summary: Nearly one-third of proteins are initially targeted to the endoplasmic reticulum (ER) membrane, where they are correctly folded and then delivered to their final cellular destinations. To prevent the accumulation of misfolded membrane proteins, ER-associated degradation (ERAD) moves these clients from the ER membrane to the cytosol, a process known as retrotranslocation. Our recent work in Saccharomyces cerevisiae reveals a derlin rhomboid pseudoprotease, Dfm1, is involved in the retrotranslocation of ubiquitinated ERAD membrane substrates. In this study, we identify conserved residues of Dfm1 that are critical for retrotranslocation. We find several retrotranslocation-deficient Loop 1 mutants that display impaired binding to membrane substrates. Furthermore, Dfm1 possesses lipid thinning function to facilitate in the removal of ER membrane substrates, and this feature is conserved in its human homolog, Derlin-1, further implicating that derlin-mediated retrotranslocation is a well-conserved process.
