What is IRE1 Alpha?

The IRE1 alpha protein is a single-pass, type I membrane protein within the ER that functions as a sensor of unfolded ER proteins. It is ubiquitously expressed, with highest levels notably in the pancreas.

What type of protein is IRE1?

ER transmembrane protein
As an ER transmembrane protein, IRE1 monitors ER homeostasis through an ER luminal stress-sensing domain and triggers UPR through a cytoplasmic kinase domain and an RNase domain [15, 16].

What is Ridd biology?

Ire1 also cleaves other mRNAs localized to the ER membrane through regulated Ire1-dependent decay (RIDD). We find that during acute ER stress in mammalian cells, Xbp1-like SLs within the target mRNAs are necessary for RIDD. This coordination between Perk and Ire1 may serve to spatially and temporally regulate RIDD.

What is perk biology?

PRKR-like endoplasmic reticulum kinase (PERK) is an ER protein that regulates the unfolded protein response, but it has also been implicated in other cellular processes, including calcium (Ca2+) signalling.

How is Ire1 activated?

Ire1 is activated in response to accumulation of misfolded proteins within the endoplasmic reticulum as part of the unfolded protein response (UPR). It is a unique enzyme, possessing both kinase and RNase activity that is required for specific splicing of Xbp1 mRNA leading to UPR activation.

Is Ire1 a kinase?

IRE1 is a key component of the UPR signaling pathway and has dual protein kinase (PK) and RNase activities.

How is IRE1 activated?

What diseases does the endoplasmic reticulum cause?

There is accumulating evidence implicating prolonged ER stress in the development and progression of many diseases, including neurodegeneration, atherosclerosis, type 2 diabetes, liver disease, and cancer.

What is PERK gene?

PKR-like ER kinase (PERK, EIF2AK3) is an elF2alpha kinase that inhibits protein translation. PERK is a type one endoplasmic reticulum (ER) membrane protein which is involved in both the integrated stress response (ISR) and unfolded protein response (UPR).

How is Ire1 regulated by BiP?

One model proposes that Ire1 activity is mainly regulated by the ER-resident chaperone BiP (Kar2 in yeast). In this model, BiP inhibits Ire1 activity by binding to it in the absence of stress. During stress, BiP is titrated away by unfolded proteins, leaving Ire1 free to oligomerize and activate.

How does JNK activate chaperone genes?

Mammalian homologs of yeast IRE1, which activate chaperone genes in response to ER stress, also activated JNK, and IRE1alpha-/- fibroblasts were impaired in JNK activation by ER stress. The cytoplasmic part of IRE1 bound TRAF2, an adaptor protein that couples plasma membrane receptors to JNK activation.

Does TRAF2 inhibit JNK activation by Ire1?

Dominant-negative TRAF2 inhibited activation of JNK by IRE1. Activation of JNK by endogenous signals initiated in the ER proceeds by a pathway similar to that initiated by cell surface receptors in response to extracellular signals.

What type of protein is IRE1α?

IRE1α is a type I transmembrane protein with a protein serine/threonine kinase and endoribonuclease domain. Activation of IRE1α occurs when the ER chaperone BiP is released from its luminal domain when a build-up of unfolded proteins arises [1,5,11].

Does the ire1/jnk pathway mediate inflammation in TEC?

IRE1/JNK stable knock-down in HK-2 cells and shRNA-mediated STAT3 depletion in HRMC confirmed their role in inflammation/glomerulosclerosis. These findings suggest that IRE1/JNK pathway mediates inflammation in TEC, affecting mesangial cells.