Researchers from IISc identify and shed light on the role of protein complexes that play key roles in transporting synthesizing enzymes that aid melanin production in cells.
Delivery of cargo to the correct address requires accurate directions and a dependable machinery for delivery. Any defects in them affect timely delivery or cause the cargo to be misdelivered. This chain of events is not very different at a cellular level. Our cells also have their own transport pathways responsible for the cargo delivery at the right destination at the right time. Any variations to that system shows up as symptoms to fatal diseases. A team of researchers from the Indian Institute of Science (IISc), Bangalore unravels the nitty gritties of one such transport pathway in specialized animal cells where failure to deliver the cargo— melanin synthesizing enzymes in this case — could result in disorders like albinism.
Melanin pigments are responsible for the colour of our skin and also play an important role in protection against radiations and any other damage from light. They are produced by a series of organic chemical reactions that occur in cellular organelles called melanosomes. These cell compartments need melanin synthesizing enzymes transported from other organelles to non-pigmented premature melanosomes where pigment production is initiated. The cargo transport pathways are facilitated with the help of four multi subunit cytosolic protein complexes, BLOC‑1, ‑2, ‑3 and adaptor protein (AP)-3 complex.
BLOC‑1 consists of 8 subunits, functioning in the initial step of transport pathway, while BLOC‑2, a 3‑subunit protein complex, functions towards the end of the pathway. The team of researchers led by Subba Rao Gangi Setty from the Department of Microbiology and Cell Biology in IISc recently elucidated the role of BLOC‑2 in directing the cargo containing vesicles towards maturing melanosomes for subsequent reactions. It does so by the specific method of “tethering” or by stabilizing the two different membranes between which the cargo is transferred through fusion and subsequent cargo delivery.
They went on to show that mutations in any protien subunit of BLOC‑2 result in inefficient delivery of melanin synthesizing proteins to maturing melanosomes and thus failure in production of the melanin pigment. This malfunction manifests in the form of albinism of skin and eye, also referred to as occulocutaneous albinism. This is one of the primary clinical symptoms in Hermansky-Pudlak Syndrome (HPS). The other symptoms are lung fibrosis and bleeding. Out of the 16 possible genetic mutations that can result in HPS, only 9 are known in humans so far. Three out of those nine subtypes are a result of mutations in the BLOC‑2 protein complex.
Even though it is now established that BLOC‑1 and‑2 play key respective roles in the overall cargo delivery, how they achieve this is not yet clear. In addition to these key proteins, other cellular machineries are also known to be responsible for membrane fusion and cargo delivery. These proteins are called Soluble NSF (N-ethylmaleimide-sensitive factor)Attachment Protein REceptor (SNARE). SNARE proteins, a family of about 38 proteins has been known for their role in membrane fusion during the delivery of cargo. For the first time, the researchers have identified two members from the SNARE family that are involved in the protein transport pathways to melanosomes. Loss in expression of these proteins mistarget and degarde the enzymes, subsequently affecting melanosome maturation. The team demonstrated that higher expression of a mutant form of SNARE increased cell pigmentation. Furthermore, their study has also shown how these molecules recycle and regulate each other for efficient cargo delivery and melanosome formation.
The team intends to further work on uncovering the details of the intramolecular interactions between the SNAREs, BLOC‑1/-2 complexes and other key players involved in the transport pathway. It is important to understand the recruitment of these molecules onto the membranes during maturation of melanosomes. This would help in understanding the formation of other organelles such as dense granules in platelets and lamellar bodies in Type II lung epithelial cells, which are also defective in some HPS patients. Moreover, such studies will illustrate the mechanism of organelle formation in addition to understanding the etiology of an autosomal recessive disorder.