Abstract
Glycolipid transfer proteins (GLTPs) were first identified over three decades ago as ~24kDa, soluble, amphitropic proteins that specifically accelerate the intermembrane transfer of glycolipids. Upon discovery that GLTPs use a unique, all-α-helical, two-layer ‘sandwich’ architecture (GLTP-fold) to bind glycosphingolipids (GSLs), a new protein superfamily was born. Structure/function studies have provided exquisite insights defining features responsible for lipid headgroup selectivity and hydrophobic ‘pocket’ adaptability for accommodating hydrocarbon chains of differing length and unsaturation. In humans, evolutionarily-modified GLTP-folds have been identified with altered sphingolipid specificity, e. g. ceramide-1-phosphate transfer protein (CPTP), phosphatidylinositol 4-phosphate adaptor protein-2 (FAPP2) which harbors a GLTP-domain and GLTPD2. Despite the wealth of structural data (>40 Protein Data Bank deposits), insights into the in vivo functional roles of GLTP superfamily members have emerged slowly. In this review, recent advances are presented and discussed implicating human GLTP superfamily members as important regulators of: i) pro-inflammatory eicosanoid production associated with Group-IV cytoplasmic phospholipase A2; ii) autophagy and inflammasome assembly that drive surveillance cell release of interleukin-1β and interleukin-18 inflammatory cytokines; iii) cell cycle arrest and necroptosis induction in certain colon cancer cell lines. The effects exerted by GLTP superfamily members appear linked to their ability to regulate sphingolipid homeostasis by acting in either transporter and/or sensor capacities. These timely findings are opening new avenues for future cross-disciplinary, translational medical research involving GLTP-fold proteins in human health and disease. Such avenues include targeted regulation of specific GLTP superfamily members to alter sphingolipid levels as a therapeutic means for combating viral infection, neurodegenerative conditions and circumventing chemo-resistance during cancer treatment.
| Original language | English (US) |
|---|---|
| Article number | 101031 |
| Journal | Progress in Lipid Research |
| Volume | 78 |
| DOIs | |
| State | Published - Apr 2020 |
Bibliographical note
Funding Information:We are grateful to Xin Lin, Taeowan Chung, and Helen Pike for their pioneering molecular biological and cell biological studies of GLTP and CPTP as members of the REB lab. Our studies also benefited from collaborative research on the plant CPTP orthologue, ACD11, with the John Mundy lab via Nikolaj Petersen, Daniel Hofius, and David Munch. We are thankful for biophysical studies carried out by Xiuhong Zhai, Dhirendra Simanshu, Ivan Boldyrev, Ravi-Kanth Kamlekar, Roop Kenoth, Margarita Malakhova, Chetan Rao, Xin-Min Li, and Peter Mattjus as well as to other long-standing collaborators (Julian G. Molotkovsky and Dinshaw J. Patel) who played key roles in elucidating GLTP-fold structure/function relationships. We especially appreciate the long-term interest and support of GLTP superfamily research by Dr. Jean Chin while administering NIH RO1-GM45928 and also are grateful for support received from RO1-CA121493, RO1-HL125353, Southern Minnesota Paint-the-Town-Pink Grant Awards, and the Hormel Foundation.
Funding Information:
We are grateful to Xin Lin, Taeowan Chung, and Helen Pike for their pioneering molecular biological and cell biological studies of GLTP and CPTP as members of the REB lab. Our studies also benefited from collaborative research on the plant CPTP orthologue, ACD11, with the John Mundy lab via Nikolaj Petersen, Daniel Hofius, and David Munch. We are thankful for biophysical studies carried out by Xiuhong Zhai, Dhirendra Simanshu, Ivan Boldyrev, Ravi-Kanth Kamlekar, Roop Kenoth, Margarita Malakhova, Chetan Rao, Xin-Min Li, and Peter Mattjus as well as to other long-standing collaborators (Julian G. Molotkovsky and Dinshaw J. Patel) who played key roles in elucidating GLTP-fold structure/function relationships. We especially appreciate the long-term interest and support of GLTP superfamily research by Dr. Jean Chin while administering NIH RO1-GM45928 and also are grateful for support received from RO1-CA121493 , RO1-HL125353 , Southern Minnesota Paint-the-Town-Pink Grant Awards , and the Hormel Foundation .
Publisher Copyright:
© 2020 Elsevier Ltd
Keywords
- Autophagy
- Cytokines
- Eicosanoids
- Glycolipid transfer protein superfamily
- Inflammasomes
- Necroptosis
- Phosphoglyceride regulatory binding
- Sphingolipid homeostasis
- Sphingolipid rheostat
