A researcher isolated a mutant of an ER resident protein-folding enzyme (PFE) that has lost its KDEL sequence (ER retention sequence). Potential consequences of such a mutation are given below.

A. PFE is found in the extracellular space
B. PFE is degraded in the ER
C. Unfolded proteins increase in the ER
D. PFE is transported to the cytosol

Which one of the following options represents the combination of all correct statements?

Correct option is C

Understanding the KDEL Sequence:

• KDEL sequence is a signal found at the C-terminus of proteins that reside in the ER. It helps retain the proteins in the ER and prevent them from being secreted out of the cell.

• ER resident proteins like PFE (protein-folding enzyme) are critical for proper protein folding inside the ER. If the KDEL sequence is lost, the protein can no longer stay in the ER and may be mislocalized, degraded, or cause other cellular issues.

Analyzing the Statements:

1. A: "PFE is found in the extracellular space."

   • Correct: When a protein like PFE loses its KDEL sequence, it fails to be retained in the ER. As a result, it could be transported to the Golgi apparatus and eventually secreted out of the cell. Hence, it is possible for the protein to end up in the extracellular space.

   • Conclusion: This statement is correct.

2. B: "PFE is degraded in the ER."

   • Incorrect: When the KDEL sequence is lost, the PFE protein will likely be mislocalized rather than degraded directly in the ER. The loss of retention does not necessarily mean that the protein will be degraded in the ER. Proteins are typically degraded if they are misfolded, and this degradation usually happens through the ER-associated degradation (ERAD) pathway, but B is not the most accurate explanation for the loss of KDEL sequence.

3. C: "Unfolded proteins increase in the ER."

   • Correct: Losing the KDEL sequence could lead to the misfolding of PFE or other proteins that should have been folded in the ER. Misfolded or unfolded proteins accumulate in the ER, triggering the unfolded protein response (UPR). This would be consistent with the increase of unfolded proteins in the ER, and this is a valid consequence of the mutation.

4. D: "PFE is transported to the cytosol."

   • Incorrect: If PFE is not retained in the ER, it would likely be transported through the Golgi apparatus and potentially secreted outside the cell. It is unlikely to be transported to the cytosol, as proteins that fail to localize properly often face degradation pathways rather than being transported to the cytosol. Hence, this statement is less relevant in this case.

Correct Answer:

• The correct combination is Option 3: A and C, where:

  • A (PFE is found in the extracellular space) is true because loss of the KDEL sequence may result in PFE being secreted.

  • C (Unfolded proteins increase in the ER) is true because loss of the KDEL sequence can lead to the accumulation of misfolded proteins in the ER, triggering the UPR.

Final Answer: Option 3: A and C.