Effects Of IRAK2-Smurf1 Axis On Endoplasmic Reticulum Stress Responses

Endoplasmic reticulum(ER) was characteristic by an arena and a regulator of Ca2+ storage and homeostasis, as well as protein decoration and synthesis, all of which are extremely sensitive to a lot of environmen- -tal, physiological, and pathophysiological conditions.The ER is one of the most important membranes in the cell,which contains a number of Ca2+ regulated molecular chaperones and responsible for the proper folding of proteins.The accumulation of unfolding protein or disruption of Ca2+ storage and homeostasis or physiological abnormalities,such as starvation, anoxia, pharmaceutic effect,leads a kind of turbulence in cellular energy or nutrient homeostasis which we also called ER stress. There is increas--ing evidence linking endoplasmic reticulum stress with the development of diseases,such as Alzhemer’s disease, diabetes,Renal tubular injury, Parkinson’s disease,etc. ER stress promotes apoptosis mainly through Ca2+ signals pathway and unfolded protein response pathway. The motiv--ation of ER stress is designed to promote cell survival.For example,The unfolded protein response (UPR) pathway is activated by the accumulati--on of unfolded proteins, ultimately in order to reset the ER function. When the UPR was come out,the ER can transfer its signals by three ER transmembrane proteins:inositol-requiring en-zyme 1 (IRE1), activating transcription factor 6 (ATF6) and dsRNA-activated protein kinase-like ER kinase (PERK).Ubiquitylation was defined as an multi-step enzymatic process. Its function was first discover as a terminator which makes selected target proteins marked by ubqiutin then the ubiquitintagged proteins will be degradate by 26s proteasome system. With the development of research, additional functions of ubiquitylation have been found, which contains sub-cellular protein locating and transfer, and cell signal transduction. It also take part in many dysfunctions and disorders in the physical process such as cell proliferation, cell differentiation, apoptosis, transcription regulation, injury repair and immune response.The ubiquitin-proteasome system (UPS)consisting essentially of ubiquitin-activating enzyme (El), ubiquitin-conjugating enzyme (E2), ubiquitin protein ligase (E3) and the 26s proteasome system. E3 ligases are categorized into two main catalogs:homologous to E6AP C-terminal domain containing ligases which be called HECT E3s for short and the really interesting new gene(RING) domain containing ligases which be called RING E3s for short.We get the cognition of HECT E3s mostly from the studies of Nedd4 family E3s.As one of Nedd4 family members, Smad ubiquitination regulatory factor 1 (Smurfl)was firstly identified as an E3 ligase of TGF-β7BMP pathway. With the increasing number of researches on Smurfl,it has been found that Smurfl is existed in many organs,such as the brain,the heart, lungs, bone,the nervous system,acting as a physiological regulator.In 2005,one Science paper reported a series of proteins may be able to interact with Smurf1.Among these series of proteins,IRAK2 was predicted to be an interacting partner of Smurf1.However,the biochemical and physiological functions of the interaction between IRAK2 and Smurfl has not been investigated.Interleukin-1 receptor associated kinase (IRAKs) is an critical regulator of Toll like receptor pathway.The IRAKs family contains 4 members:IRAK 1,IRAK2,IRAK3 and IRAK4. All the family members have a death domain(DD),which can interact with the other DD comes from MyD88.In this study,We first demonstrated that IRAK2 specifically interacts with Smurf1.However,Smurfl was not the E3 of IRAK2.We found that IRAK2 can degradation Smurfl by phosphorylation its threonine site.After all,we detect the degree of downstream proteins in ER stress signal pathway using stimulant Thapsigargin.The ER stress occurred after being stimulate by Thapsigargin,then we found that the downstream proteins were down regulated.Our research may reveal a cross talk between IRE1 pathway and ATF6 pathway.