The Schekman lab has focused on the mechanism of membrane assembly and secretion, initially with a genetic and biochemical dissection of the process in S. cerevisiae. The SEC genes we discovered control each of the stages in a pathway of secretion that is evolutionarily conserved from yeast to humans. Among the many genes we identified, a set (Sec61, 62, 63, 71 and 72) were found to encode protein subunits of a polypeptide translocation channel responsible for the import of newly-synthesized soluble and membrane cargo proteins into the endoplasmic reticulum (ER) en route to various destinations in or out of the cell. Our research group also discovered the coat protein complex, COPII, responsible for the selective capture of cargo and morphogenesis of transport vesicles that convey membrane and soluble proteins from the ER to the Golgi complex. In more recent years, our efforts have turned to a cellular and biochemical analysis of membrane traffic in mammalian, primarily human, cells grown in cell culture.

Our current interests have focused on the unconventional secretion of certain proteins that lack a signal peptide and thus must be translocated across a membrane by some novel mechanism independent of the Sec61 channel. Most recently, we have analyzed the path taken by alpha-synuclein (a-syn), a small relatively unstructured protein that is genetically implicated in Parkinson’s Disease (PD). We have identified a path that involves a-syn translocation into the endosome which by fusion at the cell surface results in a-syn secretion. Work in progress has uncovered a set of endosomal membrane proteins that may create a channel for the novel translocation event. This novel path may be responsible for the pathological spread of alpha-synuclein in the brain of patients afflicted with PD.

All cells, even bacterial cells, also secrete vesicles. Two types of extracellular vesicles (EVs), microvesicles and exosomes are secreted by mammalian cells in vivo and in vitro. We have evaluated the molecular mechanism by which certain RNA-binding proteins and micro RNAs are captured into exosomes for secretion by cultured mammalian cells. In recent work we found that conditions of stress and damage to the cell surface result in a substantial stimulation of microvesicle and exosome secretion as a by-product of a plasma membrane repair process. Another current effort has focused on the role that EVs may play in intercellular communication. In one recent study, we reported that open-ended intercellular tubular membrane connections, particularly when undifferentiated cells are paired with tumor cells, appear to be more active than exosomes as a source of intercellular protein and membrane traffic. The connections that are most active involve a membrane fusogen, syncytin, that is upregulated in tumor cells. We are now exploring the role of syncytin in exosomes secreted by tumor cells.

Schekman has taken an active role in scientific publication as the former editor-in-chief of the Proceedings of the National Academy of Sciences (PNAS) and the founding editor of eLife, an open access journal sponsored by the Howard Hughes Medical Institute, the Max Planck Society and the Wellcome Trust. Our lab is pleased to publish in those journals that offer an open access format and where all the editorial decisions are made by active scholars.

For personal and professional reasons, Schekman has been involved as the founding Scientific Director and now Chair of the Scientific Advisory Board of an international collaborative research program on the basic science of Parkinson’s Disease (ASAP).

We are committed to mentoring young scholars who seek careers in academia or industry and are proud of the achievements of many generations of successful Schekman lab graduates.